Submissions for variant NM_000264.5(PTCH1):c.1420G>A (p.Val474Ile)

gnomAD frequency: 0.00003  dbSNP: rs766898310

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472706	SCV000549074	likely benign	Gorlin syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002393129	SCV002696619	likely benign	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317219	SCV004020534	likely benign	not specified	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: PTCH1 c.1420G>A (p.Val474Ile) results in a conservative amino acid change located in the Sterol-sensing domain (IPR000731) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 359698 control chromosomes (gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1420G>A in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 33179747). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004551526	SCV004114284	uncertain significance	PTCH1-related disorder	2022-09-30	criteria provided, single submitter	clinical testing	The PTCH1 c.1420G>A variant is predicted to result in the amino acid substitution p.Val474Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-98239912-C-T). In the ClinVar database, this variant has been listed as 'uncertain' by one outside laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/409176/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.