ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.557G>A (p.Arg186Gln) (rs397514494)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235384 SCV000292740 likely pathogenic not provided 2015-11-01 criteria provided, single submitter clinical testing The R186Q variant in the TRPV4 gene has been reported previously in three related individuals with Charcot-Marie-Tooth type 2C (Landouré et al., 2012). R186Q was subsequently reported in an individual with congenital spinal muscular atrophy and arthrogryposis; however, this individual's unaffected mother was a carrier of the variant and the authors concluded that the variant is associated with incomplete penetrance (Echaniz-Laguna et al., 2014). Functional studies show that cells with the R186Q variant had increased cellular toxicity when compared to wild type (Landouré et al., 2012). The R186Q 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 R186Q 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, the R186Q variant is a strong candidate for a pathogenic variant; however the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc RCV000235384 SCV000615861 pathogenic not provided 2016-12-02 criteria provided, single submitter clinical testing
Invitae RCV000032600 SCV000835712 likely pathogenic Charcot-Marie-Tooth disease axonal type 2C 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 186 of the TRPV4 protein (p.Arg186Gln). The arginine residue is weakly 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 been observed in individual(s) with clinical features of TRPV4-related conditions (PMID: 22675077, 24789864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39419). This variant has been reported to affect TRPV4 protein function (PMID: 22675077). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000032600 SCV000056351 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2014-05-27 no assertion criteria provided literature only
GeneReviews RCV000202485 SCV000148049 pathogenic Neuromuscular disease 2014-04-02 no assertion criteria provided literature only
OMIM RCV000190887 SCV000245761 pathogenic Distal spinal muscular atrophy, congenital nonprogressive 2014-05-27 no assertion criteria provided literature only

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