Submissions for variant NM_021625.5(TRPV4):c.1378C>T (p.Arg460Trp)

gnomAD frequency: 0.00020  dbSNP: rs34227547

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230906	SCV000290592	likely benign	Charcot-Marie-Tooth disease axonal type 2C	2024-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000235250	SCV000293905	uncertain significance	not provided	2024-11-20	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in two individuals with Charcot-Marie-Tooth disease in published literature (PMID: 32376792); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in homozygous state in one clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 32906206, 32376792)
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173243	SCV001336325	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235250	SCV001716142	uncertain significance	not provided	2019-05-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379021	SCV002696435	likely benign	Inborn genetic diseases	2019-11-19	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	RCV000235250	SCV003821543	uncertain significance	not provided	2020-04-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547612	SCV004117152	uncertain significance	TRPV4-related disorder	2023-06-15	criteria provided, single submitter	clinical testing	The TRPV4 c.1378C>T variant is predicted to result in the amino acid substitution p.Arg460Trp. This variant was reported in two individuals with Charcot-Marie-Tooth disease. However, segregation information was not provided and the variants clinical significance was classified as uncertain (Volodarsky et al 2021. PubMed ID: 32376792). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-110232247-G-A). At this time, we interpret this variant's clinical significance as uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000235250	SCV004700713	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	TRPV4: BS2