ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.947G>A (p.Arg316His) (rs387906905)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000497541 SCV000590825 likely pathogenic not provided 2016-04-05 criteria provided, single submitter clinical testing
Invitae RCV000023430 SCV000767281 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2017-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 316 of the TRPV4 protein (p.Arg316His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy (SPSMA), distal hereditary motor neuropathy (dHMN), and arthrogryposis multiplex congenita (AMC) (PMID: 21288981, 24789864, 24319099). In one affected individual it was reported to occur de novo (PMID: 21288981) and in an affected family it was reported to segregate with disease (PMID: 24319099). ClinVar contains an entry for this variant (Variation ID: 30473). Experimental studies have shown that this missense change leads to cell death that can be reversed by a TRPV4 agonist (PMID: 21288981). A different missense substitution at this codon (p.Arg316Cys) has been determined to be pathogenic (PMID: 20037587, 20037588, 24789864, 21454511). This suggests that the arginine residue is critical for TRPV4 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000023430 SCV001368140 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
GeneDx RCV000497541 SCV001795764 pathogenic not provided 2020-10-15 criteria provided, single submitter clinical testing Observed in an individual with distal hereditary motor neuropathy and vocal paresis and was found to segregate with disease in a family with arthrogryposis multiplex congenita (Echaniz-Laguna et al., 2014; Laquerriere et al., 2014); Functional studies suggest that R316H results in a gain of function of TRPV4, causing increased intracellular calcium and decreased cell viability (Klein et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31701603, 24830047, 25256292, 24319099, 24789864, 21288981)
OMIM RCV000023430 SCV000044721 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2011-03-08 no assertion criteria provided literature only
GeneReviews RCV000202476 SCV000148066 pathogenic Neuromuscular disease 2014-04-02 no assertion criteria provided literature only
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415397 SCV000492580 pathogenic Clubfoot; EMG abnormality; Lower limb amyotrophy 2016-03-18 no assertion criteria provided clinical testing
Genesis Genome Database RCV000856932 SCV000999496 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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