ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.1912C>G (p.Pro638Ala) (rs760044422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416067 SCV000493331 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000416067 SCV000279738 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing The P638A variant in the TRPV4 gene has been reported previously in a study looking for TRPV4 variants in individuals with inherited neuropathies and control individuals; P638A was detected in a control individual (Fawcett et al., 2012). The P638A variant 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. The P638A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P638A as a variant of uncertain significance,
Invitae RCV000687240 SCV000814797 uncertain significance Charcot-Marie-Tooth disease type 2C 2018-04-17 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 638 of the TRPV4 protein (p.Pro638Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs760044422, ExAC 0.004%). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 234727). 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.

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