ClinVar Miner

Submissions for variant NM_000264.5(PTCH1):c.4303G>A (p.Val1435Met)

gnomAD frequency: 0.00001  dbSNP: rs587778632
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000761023 SCV000890938 uncertain significance Retinoblastoma 2016-03-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV001022254 SCV001183969 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-16 criteria provided, single submitter clinical testing The p.V1435M variant (also known as c.4303G>A), located in coding exon 23 of the PTCH1 gene, results from a G to A substitution at nucleotide position 4303. The valine at codon 1435 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001036592 SCV001199965 uncertain significance Gorlin syndrome 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1435 of the PTCH1 protein (p.Val1435Met). This variant is present in population databases (rs587778632, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 135107). 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 with a negative predictive value of 95%. 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.
ITMI RCV000121902 SCV000086106 not provided not specified 2013-09-19 no assertion provided reference population

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