Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000226160 | SCV000284337 | pathogenic | Gorlin syndrome | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1132 of the PTCH1 protein (p.Ser1132Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a personal and/or family history of basal cell nevus syndrome (PMID: 11231326, 23951062; Invitae). ClinVar contains an entry for this variant (Variation ID: 237478). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTCH1 protein function. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000226160 | SCV002819524 | likely pathogenic | Gorlin syndrome | 2022-12-14 | criteria provided, single submitter | clinical testing | Variant summary: PTCH1 c.3394T>C (p.Ser1132Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes. c.3394T>C has been reported in the literature in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) (e.g. Reifenberger_2001, Shimada_2013, Morita_2015). These data indicate that the variant may be associated with disease. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.848ins817-847). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however, another amino acid change located at the same codon (p.Ser1132Tyr in Chidambaram_1996) has been reported in association with Nevoid Basal Cell Carcinoma Syndrome suggesting the functional relevance of this residue to overall protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |