ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.2605G>A (p.Ala869Thr) (rs138396764)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197485 SCV000255062 uncertain significance Charcot-Marie-Tooth disease type 2C 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 869 of the TRPV4 protein (p.Ala869Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs138396764, ExAC 0.01%) but has not been reported in the literature in individuals with a TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 216733). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000215795 SCV000279498 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing The A869T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A869T variant is not observed at a significant frequency in large population cohorts (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.
Illumina Clinical Services Laboratory,Illumina RCV000339075 SCV000375876 uncertain significance Brachyolmia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399774 SCV000375877 uncertain significance Scapuloperoneal spinal muscular atrophy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000303968 SCV000375878 uncertain significance Charcot-Marie-Tooth disease, type 2 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000363721 SCV000375879 uncertain significance Metatrophic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000269145 SCV000375880 uncertain significance Spondylometaphyseal dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000310273 SCV000375881 uncertain significance Distal spinal muscular atrophy, congenital nonprogressive 2016-06-14 criteria provided, single submitter clinical testing

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