ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.944G>A (p.Arg315Gln) (rs1064795696)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486469 SCV000571735 likely pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing A novel R315Q variant that is likely pathogenic has been identified in the TRPV4 gene. The R315Q 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 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 TRPV4 variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Missense variants in the same residue (R315W) and a nearby residue (R316C, R316H) have been reported in the Human Gene Mutation Database in association with TRPV4-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000823337 SCV000964191 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 315 of the TRPV4 protein (p.Arg315Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 422303). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Arg315 amino acid residue in TRPV4 have been observed in affected individuals (PMID: 20037588, 21115951, 20460441, 22065612, 22702953, 21454511). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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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