ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.694C>T (p.Arg232Cys) (rs387906904)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000236017 SCV000255845 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/251028 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. One de novo case without parental identity confirmed.
GeneDx RCV000236017 SCV000293205 pathogenic not provided 2017-07-19 criteria provided, single submitter clinical testing The R232C pathogenic variant in the TRPV4 gene has been reported previously in multiple individuals with TRPV4-related disorders, including distal hereditary motor neuropathy, scapuloperoneal spinal muscular atrophy, distal spinal muscular atrophy, and Charcot-Marie-Tooth disease type 2C (Klein et al., 2011; Fiorillo et al., 2012; Echaniz-Laguna et al., 2014). The R232C variant has also been reported in two related asymptomatic individuals with abnormalities detected only on electrophysiologic testing, and in another unrelated individual who was clinically unaffected, suggesting that this variant is associated with variable expressivity and reduced penetrance (Zimon et al, 2010; Klein et al., 2011). The R232C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R232C variant is a non-conservative amino acid substitution at a position that is conserved across species. Functional studies show that the R232C variant significantly weakens the ATP- binding ability of TRPV4 (Inada et al., 2012). We interpret R232C as a pathogenic variant
Invitae RCV000023429 SCV000549245 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 232 of the TRPV4 protein (p.Arg232Cys). 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 (rs387906904, ExAC no frequency). This variant has been reported in several individuals and families affected with TRPV4-related neuropathy, including Charcot-Marie-Tooth disease type 2C, distal hereditary motor neuropathy, and scapuloperoneal spinal muscular atrophy (PMID: 20460441, 21288981, 24789864, 26048687), but exhibits reduced penetrance as it has also been observed in three clinically asymptomatic or unaffected relatives (PMID: 20460441, 26048687). This variant has also been shown to arise de novo in an individual affected with distal spinal muscular atrophy (PMID: 22526352). ClinVar contains an entry for this variant (Variation ID: 30472). Experimental studies have shown that this missense change impairs ATP-binding and cellular viability in vitro (PMID: 22702953, 21288981). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001172888 SCV001335963 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
OMIM RCV000023429 SCV000044720 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2012-01-31 no assertion criteria provided literature only
GeneReviews RCV000202445 SCV000148054 pathogenic Skeletal dysplasia; Neuromuscular disease 2014-04-02 no assertion criteria provided literature only
OMIM RCV000190886 SCV000245760 pathogenic Distal spinal muscular atrophy, congenital nonprogressive 2012-01-31 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789594 SCV000928950 uncertain significance Autosomal dominant distal hereditary motor neuropathy no assertion criteria provided literature only

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