ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.704A>G (p.Tyr235Cys) (rs754848195)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215648 SCV000279718 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing The Y235C variant in the TRPV4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y235C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y235C 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. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R232C, R232S, Q239H) 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 Y235C as a variant of uncertain significance
Invitae RCV001203030 SCV001374176 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 235 of the TRPV4 protein (p.Tyr235Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs754848195, ExAC 0.003%). This variant has not been reported in the literature in individuals with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 234711). 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: "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.

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