ClinVar Miner

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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