Submissions for variant NM_021625.4(TRPV4):c.1390C>T (p.Arg464Cys) (rs373049874)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235458	SCV000294123	uncertain significance	not provided	2016-04-25	criteria provided, single submitter	clinical testing	The R464C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R464C 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Illumina Clinical Services Laboratory,Illumina	RCV000375804	SCV000376014	uncertain significance	Charcot-Marie-Tooth disease, type 2	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000284090	SCV000376015	uncertain significance	Distal spinal muscular atrophy, congenital nonprogressive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000341387	SCV000376016	uncertain significance	Spondylometaphyseal dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000405687	SCV000376017	uncertain significance	Scapuloperoneal spinal muscular atrophy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000287694	SCV000376018	uncertain significance	Brachyolmia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000344778	SCV000376019	uncertain significance	Metatrophic dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000645552	SCV000767302	uncertain significance	Charcot-Marie-Tooth disease type 2C	2017-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 464 of the TRPV4 protein (p.Arg464Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs373049874, ExAC 0.01%). This variant has not been reported in the literature in individuals with TRPV4-related disease. ClinVar contains an entry for this variant (Variation ID: 246534). 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.