ClinVar Miner

Submissions for variant NM_021625.5(TRPV4):c.1549A>G (p.Thr517Ala)

gnomAD frequency: 0.00002  dbSNP: rs1085307827
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489529 SCV000577390 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing The T517A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T517A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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; however, 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). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV001361067 SCV001557028 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2021-06-03 criteria provided, single submitter clinical testing 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. 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"). This variant has not been reported in the literature in individuals with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 426840). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 517 of the TRPV4 protein (p.Thr517Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine.

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