ClinVar Miner

Submissions for variant NM_021625.5(TRPV4):c.2554C>T (p.Arg852Cys)

gnomAD frequency: 0.00002  dbSNP: rs372583866
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001062609 SCV001227423 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2022-08-24 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRPV4 protein function. ClinVar contains an entry for this variant (Variation ID: 857016). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792; Invitae). This variant is present in population databases (rs372583866, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 852 of the TRPV4 protein (p.Arg852Cys).
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173242 SCV001336324 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276608 SCV002567113 uncertain significance Connective tissue disorder 2022-03-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003433006 SCV004117011 uncertain significance TRPV4-related condition 2023-02-27 criteria provided, single submitter clinical testing The TRPV4 c.2554C>T variant is predicted to result in the amino acid substitution p.Arg852Cys. This variant was reported as a variant of uncertain significance in an individual with Charcot-Marie-Tooth disease (Table S2 - Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-110221488-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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