Submissions for variant NM_021625.4(TRPV4):c.943C>T (p.Arg315Trp) (rs267607143)

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Total submissions: 9

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000005291	SCV000255847	pathogenic	Charcot-Marie-Tooth disease type 2C	2013-06-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000236487	SCV000292701	pathogenic	not provided	2018-04-27	criteria provided, single submitter	clinical testing	The R315W missense pathogenic variant in the TRPV4 gene has been reported previously in association with scapuloperoneal spinal muscular atrophy and CMT2C with vocal cord paresis and short stature (Auer-Grumbach et al., 2010; Chen et al., 2010). Functional studies show that R315W alters the localization of the TRPV4 protein to the cell surface (Auer-Grumbach et al., 2010) and alters the channel function by increasing basal activity, leading to increased cell death (Inada et al., 2012). The R315W variant alters a highly conserved position predicted to be within the ankyrin repeat domain of the TRPV4 protein, where other missense pathogenic variants associated with CMT2C have been reported (Stenson et al., 2014). Therefore, the presence of the R315W pathogenic variant is consistent with a diagnosis of a TRPV4-related disorder
Invitae	RCV000005291	SCV000646256	pathogenic	Charcot-Marie-Tooth disease type 2C	2019-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 315 of the TRPV4 protein (p.Arg315Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary motor and sensory neuropathy type 2C (HMSN2C), scapuloperoneal spinal muscular atrophy (SPSMA), Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis, and congenital distal SMA in several families (PMID: 20037588, 21115951, 20460441, 22065612). ClinVar contains an entry for this variant (Variation ID: 4999). Experimental studies have shown that this missense change reduces thermal stability, alters the localization of the TRPV4 protein to the cell surface, and leads to substantially higher basal calcium levels than wild type TRPV4 (PMID: 20037588, 22702953, 21454511). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000005289	SCV000025467	pathogenic	Distal spinal muscular atrophy, congenital nonprogressive	2011-12-01	no assertion criteria provided	literature only
OMIM	RCV000005290	SCV000025468	pathogenic	Scapuloperoneal spinal muscular atrophy	2011-12-01	no assertion criteria provided	literature only
OMIM	RCV000005291	SCV000025469	pathogenic	Charcot-Marie-Tooth disease type 2C	2011-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000202514	SCV000148064	pathogenic	Neuromuscular Diseases	2014-04-02	no assertion criteria provided	literature only
GeneReviews	RCV000192244	SCV000239892	pathogenic	Charcot-Marie-Tooth disease	2015-04-30	no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000789585	SCV000928941	uncertain significance	Autosomal dominant distal hereditary motor neuropathy		no assertion criteria provided	literature only

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