Submissions for variant NM_021625.4(TRPV4):c.946C>T (p.Arg316Cys) (rs267607145)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236285	SCV000293082	pathogenic	not provided	2017-04-16	criteria provided, single submitter	clinical testing	The R316C variant in the TRPV4 gene has been reported previously in families with scapuloperoneal spinal muscular atrophy, childhood-onset distal hereditary motor neuropathy, and vocal fold paresis (Echaniz-Laguna et al., 2014; Deng et al., 2010). Additionally, studies in HEK293 and HeLa cells with the R316C variant show that this variant impacts the function of the protein (Fecto et al., 2011; Deng et al., 2010). The R316C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316C 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same codon and in nearby residues (R316H, R315W) have been reported in the Human Gene Mutation Database in association with (scapuloperoneal spinal muscular atrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R316C as a pathogenic variant.
Invitae	RCV000005294	SCV000767288	pathogenic	Charcot-Marie-Tooth disease type 2C	2018-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 316 of the TRPV4 protein (p.Arg316Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs267607145, ExAC no frequency). This variant has been reported to segregate with Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy 2C (HMSN2C) in multiple families (PMID: 20037587, 20037588, 24789864). This variant has also been shown to arise de novo in an individual affected with distal hereditary motor neuropathy (dHMN) (PMID: 24789864). ClinVar contains an entry for this variant (Variation ID: 5001). Experimental studies have shown that this missense change alters the function of TRPV4 channels and results in substantially higher basal calcium levels (PMID: 20037587, 21454511). A different missense substitution at this codon (p.Arg316His) has been determined to be pathogenic (PMID: 21288981, 24789864, 24319099). 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.
OMIM	RCV000005294	SCV000025472	pathogenic	Charcot-Marie-Tooth disease type 2C	2010-02-01	no assertion criteria provided	literature only
OMIM	RCV000005295	SCV000025473	pathogenic	Scapuloperoneal spinal muscular atrophy	2010-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000202561	SCV000148065	pathogenic	Neuromuscular Diseases	2014-04-02	no assertion criteria provided	literature only
GeneReviews	RCV000192245	SCV000239893	pathogenic	Charcot-Marie-Tooth disease	2015-04-30	no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000789587	SCV000928943	uncertain significance	Autosomal dominant distal hereditary motor neuropathy		no assertion criteria provided	literature only