Submissions for variant NM_021625.5(TRPV4):c.2396C>T (p.Pro799Leu)

dbSNP: rs121912637

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000005287	SCV000590828	pathogenic	Metatropic dysplasia	2016-06-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624630	SCV000742459	pathogenic	Inborn genetic diseases	2017-11-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707315	SCV000836406	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 799 of the TRPV4 protein (p.Pro799Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metatropic and spondylometaphyseal dysplasia (PMID: 19232556, 20425821, 20503319, 20577006, 21658220). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 4998). 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. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20425821, 21573172, 26170305, 26249260). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000707315	SCV001369422	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2019-05-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PM5,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253672	SCV001429512	pathogenic	Parastremmatic dwarfism	2017-11-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311314	SCV001501437	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000005288	SCV004013934	pathogenic	Spondyloepimetaphyseal dysplasia, Maroteaux type	2023-06-14	criteria provided, single submitter	clinical testing	PS3, PS4, PM1, PM2, PM5, PP3, PP5
GeneDx	RCV001311314	SCV004034717	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant increases the activity of the TRPV4 cation channel (Camacho et al., 2010; Loukin et al., 2011; Loukin et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19232556, 21573172, 20577006, 20425821, 26249260, 21658220, 31808622, 33710406, 20503319, 26170305)
Neuberg Centre For Genomic Medicine, NCGM	RCV003388565	SCV004100574	pathogenic	Spondylometaphyseal dysplasia, Kozlowski type		criteria provided, single submitter	clinical testing	The missense variant p.P799L in TRPV4 (NM_021625.4) has been reported previously in multiple affected indviduals with metatropic and spondylometaphyseal dyspalsia (Camacho et al,2010, Nishimura et al,2010). It is a hot spot mutation for metatropic dysplasia (Dai J et al,2010). Experimental studies have shown that this missense change results in constitutive activation of the TRPV4 protein channel (Loukin SH et al,2010; Hurd L et al, 2015). It has been submitted to ClinVar as Pathogenic.The p.P799L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P799L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 799 of TRPV4 is conserved in all mammalian species. The nucleotide c.2396 in TRPV4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000005287	SCV004123086	pathogenic	Metatropic dysplasia	2023-07-01	criteria provided, single submitter	research
OMIM	RCV000005287	SCV000025465	pathogenic	Metatropic dysplasia	2010-10-01	no assertion criteria provided	literature only
OMIM	RCV000005288	SCV000025466	pathogenic	Spondyloepimetaphyseal dysplasia, Maroteaux type	2010-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000202554	SCV000148045	not provided	Skeletal dysplasia		no assertion provided	literature only