ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.711A>G (p.Arg237=) (rs927188562)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547995 SCV000646255 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2017-07-10 criteria provided, single submitter clinical testing This sequence change affects codon 237 of the TRPV4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TRPV4 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TRPV4-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001305 SCV001158485 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing The TRPV4 c.711A>G; p.Arg237Arg variant (rs927188562), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found on only two chromosomes (2/250828 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although RNA analyses would be required to confirm this. However, TRPV4 variants previously described in Charcot-Marie-Tooth disease have primarily been gain-of-function missense variants (Klein 2011, Landoure 2010), and thus the p.Arg237Arg may not conform to the predicted mechanism of disease. However, given the lack of clinical and functional data, the significance of the p.Arg237Arg variant is uncertain at this time. References: Klein CJ et al. TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology. 2011 Mar 8;76(10):887-94. Landoure G et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010 Feb;42(2):170-4.

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