ClinVar Miner

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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