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Gene Symbol VHL
Synonyms HRCA1 | pVHL | RCA1 | VHL1
Gene Description VHL, von Hippel-Lindau tumor suppressor, is part of an E3 ubiquitin protein ligase complex, which promotes degradation of HIF-alpha and other protein targets required for cellular growth and angiogenesis (PMID: 24583008, PMID: 30194449), and plays a role in genomic stability (PMID: 31747945). VHL contributes to von Hippel-Lindau disease (PMID: 30194449, PMID: 30006056) and sporadic tumors, including clear cell renal carcinoma (PMID: 24583008, PMID: 30149673).
ACMG Incidental List v2.0:
Yes, Von Hippel-Lindau syndrome (PMID: 27854360)

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Variant Impact Protein Effect Variant Description Associated with drug Resistance
A149D missense unknown VHL A149D lies within the CCT complex-binding region of the Vhl protein (UniProt.org). A149D has been identified in the scientific literature (PMID: 19996202), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
A149T missense unknown VHL A149T lies within the CCT complex-binding region of the Vhl protein (UniProt.org). A149T demonstrates HIFa and its target gene regulation, cell cycle exit, and spheroid formation to similar levels of wild-type VHL in culture (PMID: 17526729), but also results in reduced binding to Hif1a and ubiquitination (PMID: 11865071), and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
amp none no effect VHL amplification indicates an increased number of copies of the VHL gene. However, the mechanism causing the increase is unspecified.
C162F missense loss of function VHL C162F lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). C162F leads to a loss of Vhl function as indicated by failure to bind to Elongin BC complex and inhibition of ubiquitin-dependent proteolysis in cell culture (PMID: 9447969, PMID: 11331612).
C162R missense unknown VHL C162R lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). C162R has been identified in the scientific literature (PMID: 27530247, PMID: 27034166, PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
C162W missense loss of function - predicted VHL C162W lies within the Elongin BC complex-interaction region of the Vhl protein (UniProt.org). C162W is predicted to confer a loss of function to the Vhl protein, as indicated by failure to induce protein ubiquitination in culture (PMID: 17350623).
C162Y missense unknown VHL C162Y lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). C162Y has been identified in the scientific literature (PMID: 23797736, PMID: 17264095), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
C77* nonsense loss of function - predicted VHL C77* results in a premature truncation of the Vhl protein at amino acid 77 of 213 (UniProt.org). Due to the loss of all known functional domains (PMID: 19878677), C77* is predicted to lead to a loss of Vhl protein function.
D121G missense no effect - predicted VHL D121G lies within the CCT complex-binding region of the Vhl protein (UniProt.org). D121G results in decreased binding to Elongin C, but retains Vhl interaction with CUL2, ROC1, and Elongin B, and HIF regulation in culture (PMID: 19030229, PMID: 11865071).
D121Y missense unknown VHL D121Y lies within the CCT complex-binding region of the Vhl protein (UniProt.org). D121Y has been identified in sequencing studies (PMID: 24504440), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
D126N missense loss of function - predicted VHL D126N lies within the CCT complex-binding region of the Vhl protein (UniProt.org). D126N is predicted to confer a loss of function to the Vhl protein, as indicated by impaired regulation of Hif1a in cell culture (PMID: 21454469).
del deletion loss of function VHL del indicates a deletion of the VHL gene.
E173D missense unknown VHL E173D does not lie within any known functional domains of the Vhl protein (UniProt.org). E173D has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
E186K missense unknown VHL E186K does not lie within any known functional domains of the Vhl protein (UniProt.org). E186K has been identified in the scientific literature (PMID: 28753842), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
E70* nonsense loss of function - predicted VHL E70* results in a premature truncation of the Vhl protein at amino acid 70 of 213 (UniProt.org). Due to the loss of most known functional domains (UniProt.org), E70* is predicted to lead to a loss of Vhl protein function.
F119L missense loss of function VHL F119L lies within the CCT complex-binding region and the aromatic tetrahedron core domain of the Vhl protein (UniProt.org, PMID: 23840444). F119L results in decreased Vhl protein stability as compared to wild-type, demonstrating increased misfolding and aggregation of Vhl protein in in-vitro assays (PMID: 23840444), and reduced solubility and decreased binding to Hif1a protein, and overexpression of P119L leads to a lethal phenotype in animal models (PMID: 30194449).
F136L missense loss of function VHL F136L lies within the CCT complex-binding region and the aromatic tetrahedron core domain of the Vhl protein (UniProt.org, PMID: 23840444). F136L results in decreased Vhl protein stability as compared to wild-type, demonstrating increased misfolding and aggregation of Vhl protein in in-vitro assays (PMID: 23840444), and reduced solubility and decreased binding to Hif1a protein, and overexpression of P136L leads to a lethal phenotype in animal models (PMID: 30194449).
F148fs frameshift loss of function - predicted VHL F148fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 148 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), F148fs is predicted to lead to a loss of Vhl protein function.
F76S missense unknown VHL F76S does not lie within any known functional domains of the Vhl protein (UniProt.org). F76S has been identified in the scientific literature (PMID: 18836774, PMID: 24166983), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
F91L missense unknown VHL F91L does not lie within any known functional domains of the Vhl protein (UniProt.org). F91L has been identified in the scientific literature (PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
G106V missense unknown VHL G106V lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G106V has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
G114C missense unknown VHL G114C lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G114C has been identified in the scientific literature (PMID: 27845047, PMID: 27530247, PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
G114R missense loss of function - predicted VHL G114R lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G114R is predicted to confer a loss of function to the Vhl protein, as indicated by failure to bind to Elongin BC complex and TriC in cell culture (PMID: 14636579).
G123W missense unknown VHL G123W lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G123W has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
G127V missense unknown VHL G127V lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G127V has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
G144A missense unknown VHL G144A lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G144A has been not been characterized in the scientific literature and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
G144E missense unknown VHL G144E lies within the CCT complex-binding region of the Vhl protein (UniProt.org). G144E has been identified in sequencing studies (PMID: 27998968), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
G29D missense unknown VHL G29D within the pentameric repeat region of the Vhl protein (UniProt.org). G29D has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
G39D missense unknown VHL G39D lies within the pentameric repeat region of the Vhl protein (UniProt.org). G39D has been identified in the scientific literature (PMID: 23558940), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
G93V missense unknown VHL G93V does not lie within any known functional domains of the Vhl protein (UniProt.org). G93V has been identified in the scientific literature (PMID: 24969085, Journal of Clinical Oncology 28, no. 15_suppl e15024), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
H110Q missense unknown VHL H110Q lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H110Q has been identified in the scientific literature (PMID: 12781449), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
H115N missense unknown VHL H115N lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H115N has been identified in the scientific literature (PMID: 16488999), but has not been biochemically characterized and therefore, its effect on VHL protein function is unknown (PubMed, Apr 2020).
H115Q missense loss of function - predicted VHL H115Q lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H115Q is predicted to confer a loss of function to the Vhl protein, as indicated by decreased binding to Hif-1alpha in cell culture (PMID: 28775317).
H115R missense loss of function - predicted VHL H115R lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H115R is predicted to confer a loss of function to the Vhl protein based on computer modeling, demonstrating decreased protein stability and interference with Hif1 binding (PMID: 22105711).
H115Y missense unknown VHL H115Y lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H115Y has been identified in the scientific literature (PMID: 27845047, PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
I151F missense unknown VHL I151F lies within the CCT complex-binding region of the Vhl protein (UniProt.org). I151F has been identified in the scientific literature (PMID: 10766184, PMID: 22357542), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
I151N missense unknown VHL I151N lies within the CCT complex-binding region of the Vhl protein (UniProt.org). I151N has been identified in the scientific literature (PMID: 29941223), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Mar 2020).
I151T missense unknown VHL I151T lies within the CCT complex-binding region of the Vhl protein (UniProt.org). I151T has been identified in sequencing studies (PMID: 24504440), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
I180N missense unknown VHL I180N does not lie within any known functional domains of the Vhl protein (UniProt.org). I180N has been identified in sequencing studies (PMID: 25691774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
I180V missense unknown VHL I180V does not lie within any known functional domains of the Vhl protein (UniProt.org). I180V has been identified in sequencing studies (PMID: 23606570), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
inact mut unknown loss of function VHL inact mut indicates that this variant results in a loss of function of the Vhl protein. However, the specific amino acid change has not been identified.
K171G missense loss of function VHL K171G does not lie within any known functional domains of the Vhl protein (UniProt.org). K171G confers a loss of function to the Vhl protein as demonstrated by decreased Vhl sumoylation, aberrant Vhl localization, decreased association with Alix and Endobrevin and decreased localization of Alix and Endobrevin to the spindle midbody, increase in unresolved cytokinetic bridges, and accumulation of multinucleated cells in culture, and increased tumor formation in mouse models (PMID: 21652636).
L101P missense unknown VHL L101P lies within the CCT complex-binding region of the Vhl protein (UniProt.org). L101P has been identified in the scientific literature (PMID: 19996202), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L116fs frameshift loss of function - predicted VHL L116fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 116 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), L116fs is predicted to lead to a loss of Vhl protein function.
L128H missense unknown VHL L128H lies within the CCT complex-binding region of the Vhl protein (UniProt.org). L128H has been identified in the scientific literature (PMID: 15956968), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L153P missense unknown VHL L153P lies within the CCT complex-binding region of the Vhl protein (UniProt.org). L153P has been identified in the scientific literature (PMID: 24969085, PMID: 28431395), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L158fs frameshift loss of function - predicted VHL L158fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 158 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), L158fs is predicted to lead to a loss of Vhl protein function.
L158P missense loss of function VHL L158P lies within the Elongin BC-interacting region of the Vhl protein (UniProt.org). L158P leads to decreased binding of Vhl to the Elongin BC complex and failure to activate Hif1a ubiquitination in cell culture (PMID: 10973499).
L158Q missense no effect - predicted VHL L158Q lies within the Elongin BC complex interaction region of the Vhl protein (UniProt.org). L158Q results in decreased Vhl binding to Elongin C but retains HIF regulation in culture (PMID: 26503325).
L158S missense loss of function VHL L158S lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). L158S confers a loss of function to the Vhl protein as demonstrated decreased interaction with Elongin B/C and Cul2, decreased inhibition of GLUT1 and VEGF expression under normoxic conditions (PMID: 9447969), and increased Hif2a, Glut1, Junb, and Egln3 levels in cultured cells (PMID: 16098468).
L158V missense unknown VHL L158V lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). L158V has been identified in the scientific literature (PMID: 27069690), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L163F missense unknown VHL L163F lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). L163F has been identified in the scientific literature (PMID: 17102088), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L163P missense loss of function - predicted VHL L163P lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). L163P results in impaired binding to Hif1a in an in vitro assay (PMID: 11986208), and therefore, is predicted to result in a loss of Vhl protein function.
L169P missense unknown VHL L169P does not lie within any known functional domains of the Vhl protein (UniProt.org). L169P has been identified in the scientific literature (PMID: 29126202, PMID: 24727139, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L184fs frameshift unknown VHL L184fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 184 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). L184fs has been identified in sequencing studies (Cancer Res 2016;76(14 Suppl):Abstract nr 4503), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L184P missense loss of function - predicted VHL L184P does not lie within any known functional domains of the Vhl protein (UniProt.org). L184P is predicted to confer a loss of function to the Vhl protein, as indicated by decreased binding to Elongin C and Cul2 in culture (PMID: 28775317).
L184R missense unknown VHL L184R does not lie within any known functional domains of the Vhl protein (UniProt.org). L184R has been identified in sequencing studies (PMID: 23036577, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L188P missense unknown VHL L188P does not lie within any known functional domains of the Vhl protein (UniProt.org). L188P has been identified in the scientific literature (PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L188R missense unknown VHL L188R does not lie within any known functional domains of the Vhl protein (UniProt.org). L188R has been identified in sequencing studies (PMID: 24504440), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L188V missense loss of function - predicted VHL L188V does not lie within any known functional domains of the Vhl protein (UniProt.org). L188V demonstrates similar regulation of HIF-alpha, Glut1, and cyclin D1 to wild-type Vhl (PMID: 16452184PMID: 17526729, PMID: 11331612), and has been demonstrated to both promote (PMID: 16452184) and suppress (PMID: 11331612) tumor formation; however, results in disrupted fibronectin matrix assembly (PMID: 11331612PMID: 16452184) and elevated Rwdd3 (Rsume), Prkcz (aPKC), and Junb levels in cultured cells (PMID: 16098468PMID: 30890701), and increased tumor vascularization compared to controls in mouse models (PMID: 16452184), and therefore, is predicted to lead to a loss of Vhl protein function.
L201P missense unknown VHL L201P does not lie within any known functional domains of the Vhl protein (UniProt.org). L201P has been identified in sequencing studies (PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L89H missense unknown VHL L89H does not lie within any known functional domains of the Vhl protein (UniProt.org). L89H has been identified in the scientific literature (PMID: 25583177, PMID: 24755468), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
L89P missense unknown VHL L89P does not lie within any known functional domains of the Vhl protein (UniProt.org). L89P has been identified in the scientific literature (PMID: 18836774, PMID: 28431395), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
loss unknown loss of function VHL loss indicates loss of the VHL gene, mRNA and protein.
mutant unknown unknown VHL mutant indicates an unspecified mutation in the VHL gene.
N131fs frameshift loss of function - predicted VHL N131fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 131 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), N131fs is predicted to lead to a loss of Vhl function.
N131Y missense unknown VHL N131Y lies within the CCT complex-binding region of the Vhl protein (UniProt.org). N131Y has been identified in the scientific literature (PMID: 24727139, PMID: 29172931, PMID: 26831717), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
N78D missense unknown VHL N78D does not lie within any known functional domains of the Vhl protein (UniProt.org). N78D has been identified in the scientific literature (PMID: 23224817), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
N78S missense loss of function - predicted VHL N78S does not lie within any known functional domains of the Vhl protein (UniProt.org). N78S is predicted to confer a loss of function to the Vhl protein, as indicated by failure to regulate Hif1a ubiquitination in cell culture (PMID: 11331613).
N78T missense unknown VHL N78T does not lie within any known functional domains of the Vhl protein (UniProt.org). N78T has been identified in the scientific literature (PMID: 22177731, PMID: 23298237), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
N78Y missense unknown VHL N78Y does not lie within any known functional domains of the Vhl protein (UniProt.org). N78Y has been identified in sequencing studies (PMID: 23036577), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
N90I missense loss of function - predicted VHL N90I does not lie within any known functional domains of the Vhl protein (UniProt.org). N90I is predicted to confer a loss of function to the Vhl protein, as indicated by failure to regulate Hif1a ubiquitination in cell culture (PMID: 10823831).
N90Y missense unknown VHL N90Y does not lie within any known functional domains of the Vhl protein (UniProt.org). N90Y has been identified in sequencing studies (PMID: 24727139), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
negative unknown loss of function VHL negative indicates a lack of the VHL gene, mRNA, and/or protein.
over exp none no effect VHL over exp indicates an over expression of the Vhl protein. However, the mechanism causing the over expression is unspecified.
P154L missense loss of function VHL P154L lies within the CCT complex-binding region of the Vhl protein (UniProt.org). P154L results in a loss of Vhl binding to Tbp-1 and failure to mediate hypoxia-induced Hif1a degradation in culture (PMID: 14556007).
P192S missense unknown VHL P192S does not lie within any known functional domains of the Vhl protein (UniProt.org). P192S has been identified in the scientific literature (PMID: 18836774, PMID: 26957611), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P25L missense unknown VHL P25L lies within the pentameric repeat region of the Vhl protein (UniProt.org). P25L has been identified in the scientific literature (PMID: 16884327, PMID: 25803323, PMID: 24727139), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P25S missense unknown VHL P25S lies within pentameric repeat region of the Vhl protein (UniProt.org). P25S has been identified in the scientific literature (PMID: 22655276), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P81S missense loss of function VHL P81S does not lie within any known functional domains of the Vhl protein (UniProt.org). P81S results in a loss of Vhl binding to Tceb1 and failure to regulate Hif1a degradation in culture, and growth advantage in animal tumor models (PMID: 23990666).
P81T missense unknown VHL P81T does not lie within any known functional domains of the Vhl protein (UniProt.org). P81T has been identified in sequencing studies (PMID: 21602815), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P86H missense loss of function VHL P86H does not lie within any known functional domains of the Vhl protein (UniProt.org). P86H confers a loss of function to the Vhl protein as demonstrated by failure to suppress GLUT1 expression and impaired regulatory activity of Hif1-alpha (PMID: 10535940).
P86L missense unknown VHL P86L does not lie within any known functional domains of the Vhl protein (UniProt.org). P86L has been identified in the scientific literature (PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P86R missense unknown VHL P86R does not lie within any known functional domains of the Vhl protein (UniProt.org). P86R has been identified in the scientific literature (PMID: 11257211), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
P95Q missense unknown VHL P95Q does not lie within any known functional domains of the Vhl protein (UniProt.org). P95Q has been identified in sequencing studies (PMID: 29656894), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
Q132fs frameshift loss of function - predicted VHL Q132fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 132 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), Q132fs is predicted to lead to a loss of Vhl function.
Q164R missense no effect - predicted VHL Q164R lies within the Elongin BC complex interaction region of the Vhl protein (UniProt.org). Q164R results in decreased Vhl binding to Elongin C but retains HIF regulation in culture (PMID: 26503325).
Q73E missense unknown VHL Q73E does not lie within any known functional domains of the Vhl1 protein (UniProt.org). Q73E has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
Q73H missense unknown VHL Q73H does not lie within any known functional domains of the Vhl1 protein (UniProt.org). Q73H has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
Q96* nonsense loss of function - predicted VHL Q96* results in a premature truncation of the Vhl protein at amino acid 96 of 213 (UniProt.org). Due to the loss of most known functional domains (UniProt.org), Q96* is predicted to lead to a loss of Vhl protein function.
R107G missense unknown VHL R107G lies within the CCT complex-binding region of the Vhl protein (UniProt.org). R107G has been identified in the scientific literature (PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R107P missense unknown VHL R107P lies within the CCT complex-binding region of the Vhl protein (UniProt.org). R107P has been identified in the scientific literature (PMID: 18836774, PMID: 19996202), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R161* nonsense unknown VHL R161* results in a premature truncation of the Vhl protein at amino acid 161 of 213 (UniProt.org). R161* has been identified in sequencing studies (PMID: 26111976, PMID: 28757314, PMID: 28178687, PMID: 27617348), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R161fs frameshift unknown VHL R161fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 161 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). R161fs has been identified in sequencing studies (PMID: 7881415), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R161G missense loss of function - predicted VHL R161G lies within the Elongin BC complex interaction region of the Vhl protein (UniProt.org). R161G is predicted to confer a loss of function to the Vhl protein, as indicated by failure to bind to the elongin BC complex in an in vitro assay (PMID: 10587522).
R161P missense loss of function VHL R161P lies within the Elongin BC complex interaction region of the Vhl protein (UniProt.org). R161P confers a loss of function to the Vhl protein as indicated by loss of binding to the elongin BC complex and destabilization of microtubule in culture (PMID: 10587522, PMID: 20855504).
R161Q missense unknown VHL R161Q lies within the Elongin BC complex interaction region of the Vhl protein (UniProt.org). R161Q has been identified in the scientific literature (PMID: 17102087, PMID: 14767570, PMID: 23842656, PMID: 29752349), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Mar 2020).
R167G missense unknown VHL R167G does not lie within any known functional domains of the Vhl protein (UniProt.org). R167G has been identified in the scientific literature (PMID: 18836774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R167Q missense loss of function VHL R167Q does not lie within any known functional domains of the Vhl protein (UniProt.org). R167Q leads to a loss of Vhl function as indicated by impaired Elongin C binding and inhibition of Hif2a expression in cell culture (PMID: 15574766).
R167W missense loss of function - predicted VHL R167W does not lie within any known functional domains of the Vhl protein (UniProt.org). R167W is predicted to confer a loss of function to the Vhl protein, as indicated by impaired binding to Elongin BC complex and Cul2 in cell culture (PMID: 9122164).
R177fs frameshift unknown VHL R177fs results in a change in the amino acid sequence of the Vhl protein beginning at 177 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). R177fs has been identified in sequencing studies (PMID: 22683710), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R205C missense unknown VHL R205C does not lie within any known functional domains of the Vhl protein (UniProt.org). R205C has not been characterized in the scientific literature and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R205H missense unknown VHL R205H does not lie within any known functional domains of the Vhl protein (UniProt.org). R205H has been identified in sequencing studies (PMID: 29506494, PMID: 22895193), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R64P missense loss of function - predicted VHL R64P does not lie within any known functional domains of the Vhl protein (UniProt.org). R64P demonstrates regulation of Hif2a and Glut1 similar to wild-type (PMID: 16452184, PMID: 16098468), however, results in disrupted fibronectin matrix assembly (PMID: 11331612, PMID: 16452184), and increased Prkcz (aPKC) and Junb levels in cultured cells (PMID: 16098468), and increased tumor vascularization compared to controls in mouse models (PMID: 16452184), and therefore, is predicted to lead to a loss of Vhl protein function.
R79G missense unknown VHL R79G does not lie within any known functional domains of the Vhl protein (UniProt.org). R79G has been identified in sequencing studies (PMID: 30325992), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
R79P missense loss of function - predicted VHL R79P does not lie within any known functional domains of the Vhl protein (UniProt.org). R79P is predicted to lead to a loss of Vhl function by computational modeling (PMID: 18836774).
R82P missense loss of function VHL R82P does not lie within any known functional domains of the Vhl protein (UniProt.org). R82P leads to a loss of Vhl function as indicated by impaired binding to hVdu1 and inhibition of hVdu1 ubiquitination in cell culture (PMID: 11739384).
S111N missense loss of function VHL S111N lies within the CCT complex-binding region of the Vhl protein (UniProt.org). S111N leads to a loss of Vhl function as indicated by impaired binding to Hif-alpha and inhibition of Hif1a ubiquitination (PMID: 10878807).
S111R missense loss of function VHL S111R lies within the CCT complex-binding region of the Vhl protein (UniProt.org). S111R leads to a loss of Vhl function as indicated by impaired binding to Hif1a, p300 and Tip60, and failure to transactivate p53 on DNA damage in cell culture (PMID: 22071692).
S183L missense loss of function VHL S183L does not lie within any known functional domains of the Vhl protein (UniProt.org). S183L confers a loss of function to the Vhl protein as indicated by impaired ability to regulate Hif1a degradation and function in culture (PMID: 21454469).
S38F missense unknown VHL S38F lies within the pentameric repeat region of the Vhl protein (UniProt.org). S38F has been identified in sequencing studies (PMID: 15932632), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020)
S65L missense loss of function VHL S65L does not lie within any known functional domains of the Vhl protein (UniProt.org). S65L results in a loss of Vhl binding to Hif1a and failure to mediate Hif2a degradation in culture (PMID: 15611064).
S65W missense loss of function VHL S65W does not lie within any known domains of the Vhl protein (UniProt.org). S65W leads to a loss of Vhl function as indicated by impaired binding to Hif1a and failure to target Hif2a for degradation (PMID: 15611064).
S68* nonsense loss of function - predicted VHL S68* results in a premature truncation of the Vhl protein at amino acid 68 of 213 (UniProt.org). Due to the loss of most known functional domains (UniProt.org), S68* is predicted to lead to a loss of Vhl protein function.
S68fs frameshift loss of function - predicted VHL S68fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 68 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), S68fs is predicted to lead to a loss of Vhl protein function.
S80I missense loss of function - predicted VHL S80I does not lie within any known functional domains of the Vhl protein (UniProt.org). S80I is predicted to lead to a loss of Vhl function by computational modeling (PMID: 18836774).
S80N missense unknown VHL S80N does not lie within any known functional domains of the Vhl protein (UniProt.org). S80N has been identified in the scientific literature (PMID: 22683710, PMID: 23797736, PMID: 26895810), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
S80R missense loss of function - predicted VHL S80R does not lie within any known functional domains of the Vhl protein (UniProt.org). S80R is predicted to lead to a loss of Vhl function by computational modeling (PMID: 18836774).
V130D missense unknown VHL V130D lies within the CCT complex-binding region of the Vhl protein (UniProt.org). V130D has been identified in sequencing studies (PMID: 25691774), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
V130F missense unknown VHL V130F lies within the CCT complex-binding region of the Vhl protein (UniProt.org). V130F has not been biochemically characterized, however, is predicted to lead to destabilizing of Vhl by computational modeling (PMID: 19408289), and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
V155A missense no effect - predicted VHL V155A lies within the CCT complex-binding region of the Vhl protein (UniProt.org). V155A results in decreased Vhl binding to Elongin C, but retains HIF regulation in culture (PMID: 26503325), and therefore, is predicted to have no effect on Vhl protein function.
V155fs frameshift loss of function - predicted VHL V155fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 155 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of the Elongin BC complex-binding region (UniProt.org), V155fs is predicted to lead to a loss of Vhl function.
V155M missense unknown VHL V155M lies within the CCT complex-binding region of the Vhl protein (UniProt.org). V155M has been identified in sequencing studies (PMID: 28893800, PMID: 24471421), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
V165D missense unknown VHL V165D lies within the Elongin BC complex-interacting region of the Vhl protein (UniProt.org). V165D has been identified in sequencing studies (PMID: 24727139), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
V62fs frameshift loss of function - predicted VHL V62fs results in a change in the amino acid sequence of the Vhl protein beginning at aa 62 of 213, likely resulting in premature truncation of the functional protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), V62fs is predicted to lead to a loss of Vhl protein function.
V74D missense unknown VHL V74D does not lie within any known functional domains of the Vhl protein (UniProt.org). V74D has been identified in sequencing studies (PMID: 24446253, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
V74G missense loss of function - predicted VHL V74G does not lie within any known functional domains of the Vhl protein (UniProt.org). V74G is predicted to lead to a loss of Vhl function by computational modeling (PMID: 18836774).
W117C missense loss of function VHL W117C lies within the CCT complex-binding region of the Vhl protein (UniProt.org). W117C confers a loss of function to the Vhl protein as demonstrated by weak binding with CCT resulting in improper folding of the VHL-elongin BC complex (PMID: 14636579).
W117R missense loss of function VHL W117R lies within the CCT complex-binding region of the Vhl protein (UniProt.org). W117R confers a loss of function to the Vhl protein as demonstrated by disrupted fibronectin matrix assembly (PMID: 9651579), decreased Hif1a binding and ubiquitination in in vitro assays (PMID: 11865071), and elevated Hif2a and Glut1 expression in normoxic conditions (PMID: 11865071, PMID: 17526729) and increased cell proliferation under low serum conditions in culture (PMID: 17526729).
W88* nonsense loss of function - predicted VHL W88* results in a premature truncation of the Vhl protein at amino acid 88 of 213 (UniProt.org). Due to the loss of most known functional domains (UniProt.org), W88* is predicted to lead to a loss of Vhl protein function.
W88C missense unknown VHL W88C does not lie within any known functional domains of the Vhl protein (UniProt.org). W88C has been identified in sequencing studies (PMID: 10567493), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Nov 2019).
W88L missense unknown VHL W88L does not lie within any known functional domains of the Vhl protein (UniProt.org). W88L has been identified in sequencing studies (PMID: 24727139, PMID: 29118224), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
W88R missense unknown VHL W88R does not lie within any known functional domains of the Vhl protein (UniProt.org). W88R has been identified in sequencing studies (PMID: 23036577), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
wild-type none no effect Wild-type VHL indicates that no mutation has been detected within the VHL gene.
Y112H missense loss of function VHL Y112H lies within the CCT complex-binding region of the Vhl protein (UniProt.org). Y112H confers a loss of function to the Vhl protein as demonstrated by decreased stability and impaired regulation of Hif1-alpha activity in culture (PMID: 16261165, PMID: 19030229).
Y112N missense loss of function VHL Y112N lies within the CCT complex-binding region of the Vhl protein (UniProt.org). Y112N confers a loss of function to the Vhl protein as demonstrated by reduced stability of the Vhl-Elongin B/C complex (PMID: 16261165), decreased Hif1a ubiquitination in in vitro assays (PMID: 16261165, PMID: 16407835), elevated Hif2a, Glut1, and cyclin D1 expression in normoxic conditions (PMID: 16407835, PMID: 17526729), increased cell proliferation in low serum conditions in culture (PMID: 17526729), and promotion of tumor formation in animal models (PMID: 17526729).
Y175* nonsense unknown VHL Y175* results in a premature truncation of the Vhl protein at amino acid 175 of 213 (UniProt.org). Y175* has been identified in sequencing studies (PMID: 25583177, PMID: 27422173), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
Y98C missense unknown VHL Y98C does not lie within any known functional domains of the Vhl protein (UniProt.org). Y98C has been identified in the scientific literature (PMID: 22799452), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2020).
Y98H missense loss of function - predicted VHL Y98H does not lie within any known functional domains of the Vhl protein (UniProt.org). Y98H is predicted to confer a loss of function to the Vhl protein, as indicated by defects in Hif1-alpha ubiquitination (PMID: 11331612).
Y98N missense loss of function VHL Y98N does not lie within any known functional domains of the Vhl protein (UniProt.org). Y98N confers a loss of function to the Vhl protein as demonstrated by failure to completely suppress Glut1 and defects in Hif1-alpha ubiquitination (PMID: 10823831).