ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.1139C>T (p.Thr380Met) (rs764949536)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236449 SCV000293117 uncertain significance not provided 2017-01-24 criteria provided, single submitter clinical testing The T380M variant has been previously reported as a variant of unknown significance in a patient with complex neuropathy (Antoniadi et al., 2105). The T380M variant is observed in 8/66530 (0.01%) alleles from individuals of European background, and in 16/58328 (0.03%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with TRPV4-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000461756 SCV000549247 uncertain significance Charcot-Marie-Tooth disease type 2C 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 380 of the TRPV4 protein (p.Thr380Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs764949536, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with clinically suspected inherited peripheral neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 245915). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.