ClinVar Miner

Submissions for variant NM_001083602.2(PTCH1):c.3973C>T (p.Arg1325Trp) (rs45535032)

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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 RCV000210573 SCV000263006 uncertain significance Inborn genetic diseases 2014-07-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034577 SCV000043444 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Invitae RCV000168115 SCV000218771 uncertain significance Gorlin syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1391 of the PTCH1 protein (p.Arg1391Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs45535032, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with PTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 41665). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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