ClinVar Miner

Submissions for variant NM_001083602.2(PTCH1):c.3244A>G (p.Ile1082Val) (rs369265532)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575762 SCV000674591 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000414011 SCV000492177 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PTCH1 gene. The I1148V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1148V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. However, the I1148V 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.
Invitae RCV000206748 SCV000260858 uncertain significance Gorlin syndrome 2015-09-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1148 of the PTCH1 protein (p.Ile1148Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs369265532, ExAC <0.01%) but has not been reported in the germline of affected individuals. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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