Submissions for variant NM_021625.4(TRPV4):c.616C>T (p.Arg206Cys) (rs200497189)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623486	SCV000741175	uncertain significance	Inborn genetic diseases	2015-10-23	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae	RCV000645551	SCV000767300	uncertain significance	Charcot-Marie-Tooth disease type 2C	2017-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 206 of the TRPV4 protein (p.Arg206Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200497189, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with TRPV4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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