ClinVar Miner

Submissions for variant NM_001083602.2(PTCH1):c.3943G>A (p.Val1315Met) (rs187104739)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567164 SCV000674469 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000489808 SCV000576759 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PTCH1 gene. The V1381M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1381M variant is observed in 5/63768 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the V1381M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000780653 SCV000918101 likely benign not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: PTCH1 c.4141G>A (p.Val1381Met) results in a conservative amino acid change located outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 243022 control chromosomes. The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4141G>A in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000200618 SCV000254474 uncertain significance Gorlin syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1381 of the PTCH1 protein (p.Val1381Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs187104739, ExAC 0.008%). This variant has not been reported in the literature in individuals with PTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 216388). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.