ClinVar Miner

Submissions for variant NM_021625.5(TRPV4):c.695G>A (p.Arg232His)

gnomAD frequency: 0.00001  dbSNP: rs769107613
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236974 SCV000294128 uncertain significance not provided 2016-04-08 criteria provided, single submitter clinical testing The R232H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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. This substitution occurs at a position that is conserved across species. Different missense variants in the same residue (R232C, R232S) as well as missense variants in a nearby residue (R237G, R237L) have been reported in the Human Gene Mutation Database in association with TRPV4-related disorders (Stenson et al., 2014). However, the R232H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the 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.
Invitae RCV002519834 SCV003501342 likely pathogenic Charcot-Marie-Tooth disease axonal type 2C 2021-12-18 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg232 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22526352, 22702953, 24789864, 26048687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt TRPV4 protein function. ClinVar contains an entry for this variant (Variation ID: 246538). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. This variant is present in population databases (rs769107613, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the TRPV4 protein (p.Arg232His).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV002519834 SCV004809484 uncertain significance Charcot-Marie-Tooth disease axonal type 2C 2024-04-04 criteria provided, single submitter clinical testing

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