Submissions for variant NM_000264.5(PTCH1):c.395-1G>A

gnomAD frequency: 0.00001  dbSNP: rs368869806

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000149897	SCV000196745	likely pathogenic	Gorlin syndrome	2014-06-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149897	SCV000623015	uncertain significance	Gorlin syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the PTCH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs368869806, gnomAD 0.0009%). This variant has not been reported in the literature in individuals with PTCH1-related disease. However, it has been observed in several individuals who do not exhibit clinical features consistent with PTCH1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 162510). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 3 (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Undiagnosed Diseases Network, NIH	RCV000149897	SCV000746634	pathogenic	Gorlin syndrome	2016-03-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021506	SCV001183132	likely benign	Hereditary cancer-predisposing syndrome	2022-03-09	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.
GeneDx	RCV001580459	SCV001817488	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Canonical splice site variant with an unclear effect on protein function; Reported as an incidental finding identified through exome sequencing and no clinical information was provided (PMID: 25637381); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28495808, 30820324, 25637381)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000149897	SCV002032308	uncertain significance	Gorlin syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The PTCH1 c.395-1G>A intronic change results from a G to A substitution at the -1 position of intron 2 of the PTCH1 gene. This variant is predicted to result in disruption of the native splice site at c.395 and creation of an alternative splice acceptor site at c.401, where use of the alternative splice site would not result in nonsense-mediated decay or aberrant protein, but instead an in-frame deletion of two amino acids. RNA data is consistent with these predictions; half of the reads with the variant use the natural splice site at c.395 and the other half use the alternative splice junction at c.401 which results in the deletion of two amino acids (PVS1_moderate; internal data). Nonsense-mediated decay was not observed (internal data). This variant has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/8-90955480-C-A?dataset=gnomad_r2_1). This variant has not been reported in the literature in individuals with PTCH1-related disease. However, it has been observed in individuals who do not have a personal or family history of PTCH1-related disease (internal data). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PVS1_moderate, PM2_supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001580459	SCV004219237	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal PTCH1 mRNA splicing. The frequency of this variant in the general population, 0.000004 (1/251450 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with esthesioneuroblastoma (PMID: 28495808 (2017)). Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004567170	SCV005052527	uncertain significance	Basal cell carcinoma, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551300	SCV004771386	uncertain significance	PTCH1-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The PTCH1 c.395-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with recurring esthesioneuroblastoma (case 8, Gay et al. 2017. PubMed ID: 28495808). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/162510/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.