Submissions for variant NM_021625.5(TRPV4):c.956C>T (p.Ser319Leu)

gnomAD frequency: 0.00016  dbSNP: rs377518118

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235920	SCV000292910	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in two members of a single family with scapular winging, but other features of TRPV4-related disorders were not present (Brown et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541580	SCV000646257	uncertain significance	Charcot-Marie-Tooth disease axonal type 2C	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 319 of the TRPV4 protein (p.Ser319Leu). This variant is present in population databases (rs377518118, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 245783). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. 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.
Ambry Genetics	RCV002379042	SCV002695620	likely benign	Inborn genetic diseases	2021-02-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000235920	SCV003821544	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479077	SCV004223298	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: TRPV4 c.956C>T (p.Ser319Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251296 control chromosomes. c.956C>T has been reported in the literature in individuals affected with Spondylometaphyseal Dysplasia, Kozlowski Type. These report(s) do not provide unequivocal conclusions about association of the variant with Spondylometaphyseal Dysplasia, Kozlowski Type. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33303739). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV004576931	SCV005060960	uncertain significance	Neuronopathy, distal hereditary motor, autosomal dominant 8		criteria provided, single submitter	clinical testing	The missense c.956C>T (p.Ser319Leu) variant in the TRPV4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.004%) in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Benign/ Uncertain Significance. However, no details are available for independent assessment. The amino acid Serine at position 319 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser319Leu in TRPV4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004737389	SCV005366929	uncertain significance	TRPV4-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The TRPV4 c.956C>T variant is predicted to result in the amino acid substitution p.Ser319Leu. To our knowledge, this variant has not been reported in the literature in individuals with TRPV4-related disorders. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.