ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.281C>T (p.Ser94Leu) (rs201927283)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199358 SCV000255063 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2019-08-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 94 of the TRPV4 protein (p.Ser94Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201927283, ExAC 0.03%). This variant has been observed in the homozygous state in an individual with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement along with electrophysiologic findings suggestive of generalized motor axonopathy; the parents, who were both heterozygous carriers of the variant, were clinically unaffected (PMID: 31041394). ClinVar contains an entry for this variant (Variation ID: 216734). This variant has been reported to affect TRPV4 protein function (PMID: 31041394). 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.
GeneDx RCV000413068 SCV000491606 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TRPV4 gene. The S94L variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 2/33580 (0.006%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016). The S94L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense variants in nearby residues (T89I and P97R) have been reported in the Human Gene Mutation Database in association with TRPV4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in-silicoanalyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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