ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.1378C>T (p.Arg460Trp) (rs34227547)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235250 SCV000293905 uncertain significance not provided 2017-05-24 criteria provided, single submitter clinical testing The R460W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the populations of the 1000 Genomes Project. The R460W 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 silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved, and Tryptophan has been observed at this position in evolution. Additionally, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with TRPV4-related disorders (Stenson et al., 2014). Based on the currently available information, it is unclear whether the R460W variant is a pathogenic variant or a rare benign variant.
Invitae RCV000230906 SCV000290592 uncertain significance Charcot-Marie-Tooth disease type 2C 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 460 of the TRPV4 protein (p.Arg460Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34227547, ExAC 0.02%), 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 a TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 241381). 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, this variant has uncertain impact on TRPV4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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