ClinVar Miner

Submissions for variant NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)

dbSNP: rs267607149
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001331193 SCV001523177 pathogenic Brachyrachia (short spine dysplasia) 2019-05-30 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 20425821, 20577006, 21573172, 26170305, 20503319]
GeneDx RCV001549550 SCV001769727 pathogenic not provided 2019-12-16 criteria provided, single submitter clinical testing Reported previously in multiple individuals with TRPV4-related disorders including metatropic dysplasia and spondylo-epimetaphyseal dysplasia, Maroteaux-pseudo-Morquio type 2 (Camacho et al., 2010; Nishimura et al., 2010); Published functional studies demonstrate a damaging effect: increased basal activity and a reduced response to calmodulin (Loukin et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12765694, 20676052, 23143559, 20577006, 26170305, 21573172, 20503319, 20425821)
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000005303 SCV002054015 pathogenic Spondylometaphyseal dysplasia, Kozlowski type criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV001823100 SCV002073066 pathogenic Scapuloperoneal spinal muscular atrophy criteria provided, single submitter clinical testing The missense variant p.E797K in TRPV4 (NM_021625.5) has been reported in multiple affected individuals (Nishimura G et al; Dai J et al). It has been submitted to ClinVar as Pathogenic. The p.E797K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E797K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 797 of TRPV4 is conserved in all mammalian species. The nucleotide c.2389 in TRPV4 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001851964 SCV002242998 pathogenic Charcot-Marie-Tooth disease axonal type 2C 2023-08-10 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 18435). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu797 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been observed in individuals with TRPV4-related conditions (PMID: 34529350), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 21573172, 26170305). 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. This missense change has been observed in individuals with clinical features of spondylometaphyseal dysplasia (PMID: 20425821, 20503319, 20577006; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 797 of the TRPV4 protein (p.Glu797Lys).
OMIM RCV000005303 SCV000025481 pathogenic Spondylometaphyseal dysplasia, Kozlowski type 2010-10-01 no assertion criteria provided literature only
OMIM RCV000005304 SCV000025482 pathogenic Spondyloepimetaphyseal dysplasia, Maroteaux type 2010-10-01 no assertion criteria provided literature only
OMIM RCV000023424 SCV000044715 pathogenic Metatropic dysplasia 2010-10-01 no assertion criteria provided literature only
GeneReviews RCV000202566 SCV000148042 not provided Skeletal dysplasia; Neuromuscular disease no assertion provided literature only

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