Submissions for variant NM_000264.5(PTCH1):c.2266C>T (p.Leu756Phe)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002443814	SCV002737934	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-02	criteria provided, single submitter	clinical testing	The p.L756F variant (also known as c.2266C>T), located in coding exon 15 of the PTCH1 gene, results from a C to T substitution at nucleotide position 2266. The leucine at codon 756 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098764	SCV003270855	uncertain significance	Gorlin syndrome	2023-04-12	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 756 of the PTCH1 protein (p.Leu756Phe). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 1788705).
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003126251	SCV003804105	likely benign	Autism spectrum disorder	2022-02-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151408	SCV003839931	uncertain significance	not specified	2022-05-11	no assertion criteria provided	clinical testing	DNA sequence analysis of the PTCH1 gene demonstrated a sequence change, c.2266C>T, in exon 15 that results in an amino acid change, p.Leu756Phe. This sequence change does not appear to have been previously described in individuals with PTCH1-related disorders and has also not been described in population databases such as ExAC and gnomAD (dbSNP rs1398517498). The p.Leu756Phe change affects a moderately conserved amino acid residue located in a domain of the PTCH1 protein that is known to be functional. The p.Leu756Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu756Phe change remains unknown at this time.