Submissions for variant NM_021625.4(TRPV4):c.2396C>T (p.Pro799Leu) (rs121912637)

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Total submissions: 7

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children	RCV000005287	SCV000590828	pathogenic	Metatrophic 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	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae	RCV000707315	SCV000836406	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2019-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 799 of the TRPV4 protein (p.Pro799Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with metatropic and spondylometaphyseal dysplasia (PMID: 20425821, 21658220, 20503319, 20577006). It has been found to be de novo in individuals affected with metatropic dysplasia (PMID: 19232556, 20577006). ClinVar contains an entry for this variant (Variation ID: 4998). Experimental studies have shown that this missense change results in constitutive activation of the TRPV4 protein channel (PMID: 26170305, 21573172, 20425821, 26249260). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001198475	SCV001369422	pathogenic	Obesity; Brachydactyly; Skeletal dysplasia; High palate; Anteverted nares; Conductive hearing impairment; Depressed nasal bridge; Short neck; Macrocephalus; Lumbar hyperlordosis; Abnormal form of the vertebral bodies; Cuboid-shaped vertebral bodies; Disproportionate short-limb short stature; Unilateral cryptorchidism	2019-05-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM4. This variant was detected in heterozygous state.
OMIM	RCV000005287	SCV000025465	pathogenic	Metatrophic dysplasia	2010-10-01	no assertion criteria provided	literature only
OMIM	RCV000005288	SCV000025466	pathogenic	Spondyloepiphyseal dysplasia Maroteaux type	2010-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000202554	SCV000148045	pathogenic	Skeletal dysplasia	2014-04-02	no assertion criteria provided	literature only

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