Reference Detail

Ref Type
PMID (25801792)
Authors Atwood SX, Sarin KY, Li JR, Yao CY, Urman NM, Chang ALS, Tang JY, Oro AE
Title Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma.
Journal The Journal of investigative dermatology
Vol 135
Issue 8
Date 2015 Aug
URL
Abstract Text

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
A327P missense loss of function - predicted SMO A327P lies within transmembrane helix region 3 of the Smo protein (PMID: 25801792). A327P results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
C390R missense loss of function - predicted SMO C390R lies within the ligand binding pocket of the Smo protein (PMID: 25801792). C390R results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
D473G missense no effect - predicted SMO D473G lies within the ligand binding pocket of the Smo protein (PMID: 25759020). D473G does not result in activation of Smo, as indicated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, and therefore, is predicted to have no effect on Smo protein function, but has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759020, PMID: 25801792). Y
D506N missense no effect - predicted SMO D506N lies within an extracellular domain of the Smo protein (UniProt.org). D506N results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
E181K missense no effect - predicted SMO E181K lies within the FZ domain of the Smo protein (UniProt.org). E181K results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
E481G missense no effect - predicted SMO E481G lies within the ligand binding pocket of the Smo protein (PMID: 25801792). E481G results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
F605L missense loss of function - predicted SMO F605L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). F605L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
G453D missense loss of function - predicted SMO G453D lies within transmembrane helix region 6 of the Smo protein (PMID: 25801792). G453D results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
K519R missense gain of function - predicted SMO K519R lies within an extracellular domain of the Smo protein (UniProt.org). K519R results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
K564E missense loss of function - predicted SMO K564E lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). K564E results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
L221P missense loss of function - predicted SMO L221P lies within the ligand binding pocket of the Smo protein (PMID: 25801792). L221P results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
L353F missense no effect - predicted SMO L353F lies within a cytoplasmic domain of the Smo protein (UniProt.org). L353F results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
N476K missense no effect - predicted SMO N476K lies within a cytoplasmic domain of the Smo protein (UniProt.org). N476K results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
P513L missense loss of function - predicted SMO P513L lies within the ligand binding pocket of the Smo protein (PMID: 25801792). P513L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss of Smo protein function.
P688L missense loss of function - predicted SMO P688L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P688L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
P698T missense no effect - predicted SMO P698T lies within the C-Terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P698T results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
P739L missense loss of function - predicted SMO P739L lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P739L results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
P739S missense loss of function - predicted SMO P739S lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). P739S results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
R168H missense no effect - predicted SMO R168H lies within the FZ domain of the Smo protein (UniProt.org). R168H results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
R199Q missense no effect - predicted SMO R199Q lies within the NH2-terminal region of the Smo protein (PMID: 9581815). R199Q results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T336I missense no effect - predicted SMO T336I lies within transmembrane helix region 3 of the Smo protein (PMID: 25801792). T336I results in similar Hedgehog pathway signaling to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T349I missense no effect - predicted SMO T349I lies within a cytoplasmic domain of the Smo protein (UniProt.org). T349I results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T349P missense no effect - predicted SMO T349P lies within a cytoplasmic domain of the Smo protein (UniProt.org). T349P results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T534I missense loss of function - predicted SMO T534I lies within transmembrane helix region 7 of the Smo protein (PMID: 25801792). T534I results in decreased Hedgehog pathway signaling relative to wild-type Smo upon ligand addition in culture (PMID: 25801792), and therefore, is predicted to cause a loss Smo protein function.
T548I missense no effect - predicted SMO T548I lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). T548I results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
T640A missense no effect - predicted SMO T640A lies within the cytoplasmic domain of the Smo protein (UniProt.org). T640A has activity similar to wild-type Smo in cultured cells (PMID: 17287906, PMID: 25801792) and therefore, is predicted to have no effect on Smo protein function.
V386A missense no effect - predicted SMO V386A lies within the ligand binding pocket of the Smo protein (PMID: 25801792). V386A results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and therefore, is predicted to have no effect on Smo protein function.
V404M missense unknown SMO V404M lies within a helical transmembrane domain of the Smo protein (UniProt.org). The functional effect of V404M is conflicting as it demonstrates activity similar to wild-type Smo in culture (PMID: 17287906), but in another study, results in near complete loss of Hedgehog pathway signaling relative to wild-type Smo in culture (PMID: 25801792), and therefore, its effect on Smo protein function is unknown.
V414A missense no effect - predicted SMO V414A lies within helical domain 5 of the Smo protein (UniProt.org). V414A results in similar Hedgehog pathway signaling to wild-type Smo in the absence or presence of ligand in culture (PMID: 25801792), and similar cell proliferation and viability levels as wild-type Smo in culture (PMID: 29533785), and therefore, is predicted to have no effect on Smo protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMO R168H Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO R168H resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO L221P Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO L221P resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T349I Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T349I resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO V414A Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO V414A resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO K564E Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO K564E resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO K519R Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO K519R resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO C390R Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO C390R resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T548I Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T548I resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO E481G Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO E481G resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO P698T Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO P698T resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO D473G Advanced Solid Tumor resistant Vismodegib Preclinical - Cell culture Actionable In a preclinical study, mouse fibroblast cells expressing human SMO D473G were resistant to Hedgehog pathway inhibition by Erivedge (vismodegib) in culture (PMID: 25801792). 25801792
SMO E181K Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO E181K resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO R199Q Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO R199Q resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO P739L Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO P739L resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO D506N Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO D506N resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO N476K Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO N476K resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO V386A Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO V386A resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO W535L Advanced Solid Tumor resistant Vismodegib Preclinical - Cell culture Actionable In a preclinical study, mouse fibroblast cells expressing human SMO W535L were resistant to Hedgehog pathway inhibition by Erivedge (vismodegib) in culture (PMID: 25801792). 25801792
SMO V404M Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO V404M resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO A327P Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO A327P resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO G453D Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO G453D resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO P739S Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO P739S resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO L353F Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO L353F resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T640A Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T640A resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T349P Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T349P resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T336I Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T336I resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO P513L Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO P513L resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO F605L Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO F605L resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792
SMO T534I Advanced Solid Tumor no benefit Vismodegib Preclinical - Cell culture Actionable In a preclinical study, Erivedge (vismodegib) treatment of cells expressing SMO T534I resulted in Hedgehog pathway activity similar to that of wild-type Smo in culture (PMID: 25801792). 25801792