Submissions for variant NM_000264.5(PTCH1):c.1603-2A>G

dbSNP: rs1064793921

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483991	SCV000567352	pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing	The c.1603-2 A>G splice site variant in the PTCH1 gene destroys the canonical spliceacceptor site in intron 11. It is predicted to cause abnormal gene splicing, either leading toan abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormalprotein product if the message is used for protein translation. Although this exact variant has not previously been reported to our knowledge, another splice site variant at this samenucleotide position (c.1603-2 A>C) has been reported in HGMD in association with nevoidbasal cell carcinoma syndrome (Stenson et al., 2014). Therefore, we consider the c.1603-2 A>G variant to be pathogenic.
Invitae	RCV000543539	SCV000622923	pathogenic	Gorlin syndrome	2022-01-05	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1603-2A nucleotide in the PTCH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 24814739). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419508). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 of the PTCH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000543539	SCV002557688	pathogenic	Gorlin syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with basal cell nevus syndrome or Gorlin syndrome (MIM#109400). Gain of function variants have been postulated to be associated with holoprosencephaly 7 (MIM#610828; PMID: 18830227). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Families with identical genotypes have been reported with variable phenotypes (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two other variants affecting the same canonical splice site have been reported pathogenic in ClinVar, and one of these has been reported in the literature in a patient with basal cell nevus syndrome (PMID: 24814739). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported pathogenic twice in the ClinVar database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003401524	SCV004110645	pathogenic	PTCH1-related condition	2023-03-02	criteria provided, single submitter	clinical testing	The PTCH1 c.1603-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different nucleotide change at the same position (c.1603-2A>C) has been reported in an individual with nevoid basal cell carcinoma/Gorlin-Goltz syndrome (Patient 16 in Table 2, Larsen et al. 2014. PubMed ID: 24814739). Variants that disrupt the consensus splice acceptor site in PTCH1 are expected to be pathogenic. This variant is interpreted as pathogenic.