Submissions for variant NM_021625.4(TRPV4):c.137C>T (p.Ser46Phe) (rs202066574)

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Total submissions: 1

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000550504	SCV000646238	uncertain significance	Charcot-Marie-Tooth disease type 2C	2018-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 46 of the TRPV4 protein (p.Ser46Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs202066574, 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. ClinVar contains an entry for this variant (Variation ID: 469035). 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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