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

Total submissions: 8

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