ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.1390C>T (p.Arg464Cys) (rs373049874)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235458 SCV000294123 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing The R464C 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. The R464C 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 in mammals. 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Illumina Clinical Services Laboratory,Illumina RCV000375804 SCV000376014 uncertain significance Charcot-Marie-Tooth disease, type 2 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000284090 SCV000376015 uncertain significance Distal spinal muscular atrophy, congenital nonprogressive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341387 SCV000376016 uncertain significance Spondylometaphyseal dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405687 SCV000376017 uncertain significance Scapuloperoneal spinal muscular atrophy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000287694 SCV000376018 uncertain significance Brachyolmia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000344778 SCV000376019 uncertain significance Metatrophic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000645552 SCV000767302 uncertain significance Charcot-Marie-Tooth disease type 2C 2017-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 464 of the TRPV4 protein (p.Arg464Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs373049874, ExAC 0.01%). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 246534). Algorithms developed to predict the effect of missense changes on protein structure and function 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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