Submissions for variant NM_000264.5(PTCH1):c.1913G>A (p.Arg638His)

gnomAD frequency: 0.00032  dbSNP: rs145766839

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001087187	SCV000260535	benign	Gorlin syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000592243	SCV000708880	likely benign	not specified	2017-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000592243	SCV000730309	likely benign	not specified	2017-11-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756577	SCV000884424	uncertain significance	not provided	2018-01-24	criteria provided, single submitter	clinical testing	The c.1913G>A; p.Arg638His variant (rs145766839), to our knowledge, is not reported in the medical literature, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.1% (identified on 27 out of 24,020 chromosomes) and is classified as likely benign in ClinVar (ID 220182). The arginine at position 638 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Arg638His variant on protein structure and function provide conflicting information (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Arg638His variant cannot be determined with certainty.
Ambry Genetics	RCV001013676	SCV001174293	likely benign	Hereditary cancer-predisposing syndrome	2021-02-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Sema4, Sema4	RCV001013676	SCV002526829	likely benign	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003937779	SCV004750891	likely benign	PTCH1-related condition	2022-09-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).