Submissions for variant NM_000264.5(PTCH1):c.655-12_655-11insGGCCTCTTCTTTTTTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGTGAGACTGGATGGTCTGGATCTCGTGTACTCGTGATACTCCCGCCTCTGCCTCCCAAACAGCTGGGATTACAGGCGTGAGCCACTTCGCCCGGCC

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003503205	SCV004324559	likely pathogenic	Gorlin syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the PTCH1 gene. It does not directly change the encoded amino acid sequence of the PTCH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of basal cell nevus syndrome (Invitae). It has also been observed to segregate with disease in related individuals. Studies have shown that this variant results in skipping of exons 4-5, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the PTCH1 protein in which other variant(s) (p.Glu237Lys) have been observed in individuals with PTCH1-related conditions (PMID: 21514272). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.