Submissions for variant NM_021625.4(TRPV4):c.37G>T (p.Gly13Trp) (rs763302555)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237063	SCV000292777	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	The G13W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G13W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and other missense mutations 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae	RCV000458201	SCV000549252	uncertain significance	Charcot-Marie-Tooth disease type 2C	2018-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with tryptophan at codon 13 of the TRPV4 protein (p.Gly13Trp). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is present in population databases (rs763302555, ExAC 0.008%). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 245716). 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: "Possibly Damaging"; 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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