ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.805C>T (p.Arg269Cys) (rs267607146)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517563 SCV000615867 pathogenic not provided 2016-10-05 criteria provided, single submitter clinical testing
GeneReviews RCV000202537 SCV000148056 pathogenic Neuromuscular Diseases 2014-04-02 no assertion criteria provided literature only
GeneReviews RCV000192242 SCV000239890 pathogenic Charcot-Marie-Tooth disease 2015-04-30 no assertion criteria provided literature only
Invitae RCV000005296 SCV000767301 pathogenic Charcot-Marie-Tooth disease type 2C 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 269 of the TRPV4 protein (p.Arg269Cys). 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 (ExAC no frequency). This variant has been reported to segregate with TRPV4-related neuropathy in multiple affected families (PMID: 20037586, 21336783, 24789864, 26110311). It has also been reported to be de novo in affected individuals (PMID: 25900305, 24789864). Incomplete penetrance has been reported for this variant (PMID: 21336783). ClinVar contains an entry for this variant (Variation ID: 5002). Experimental studies have shown that this missense change alters the conformation of the TRPV4 channel and increases constitutive and activated channel currents (PMID: 22702953, 20037586). A different missense substitution at this codon (p.Arg269His) has been determined to be pathogenic (PMID: 20037588, 20037587, 24575025, 24963089, 26948711, 27751652). 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 RCV000005296 SCV000025474 pathogenic Charcot-Marie-Tooth disease type 2C 2011-08-01 no assertion criteria provided literature only
OMIM RCV000033215 SCV000057062 pathogenic Scapuloperoneal spinal muscular atrophy 2011-08-01 no assertion criteria provided literature only
OMIM RCV000190885 SCV000245759 pathogenic Distal spinal muscular atrophy, congenital nonprogressive 2011-08-01 no assertion criteria provided literature only

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