ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.956C>T (p.Ser319Leu) (rs377518118)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235920 SCV000292910 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing The S319L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S319L 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. The S319L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R315W, R316H, R316C) have been reported in the Human Gene Mutation Database in association with TRPV4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S319L as a variant of uncertain significance.
Invitae RCV000541580 SCV000646257 uncertain significance Charcot-Marie-Tooth disease type 2C 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 319 of the TRPV4 protein (p.Ser319Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs377518118, ExAC 0.03%), 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 TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 245783). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.

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