ClinVar Miner

Submissions for variant NM_021625.4(TRPV4):c.806G>A (p.Arg269His) (rs267607144)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623703 SCV000741621 pathogenic Inborn genetic diseases 2016-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Athena Diagnostics Inc RCV000005293 SCV000255846 pathogenic Charcot-Marie-Tooth disease type 2C 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763296 SCV000893960 pathogenic Brachyrachia (short spine dysplasia); Digital arthropathy-brachydactyly, familial; Metatrophic dysplasia; Parastremmatic dwarfism; Spondylometaphyseal dysplasia, Kozlowski type; Spondyloepiphyseal dysplasia Maroteaux type; Distal spinal muscular atrophy, congenital nonprogressive; Scapuloperoneal spinal muscular atrophy; Sodium serum level quantitative trait locus 1; Charcot-Marie-Tooth disease type 2C; Avascular necrosis of femoral head, primary, 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000235740 SCV000293511 pathogenic not provided 2017-02-13 criteria provided, single submitter clinical testing The de novo R269H pathogenic variant in the TRPV4 gene has been reported previously as a de novo varaint in a child with congenital spinal muscular atrophy with arthrogryposis and skeletal dysplasia (Echaniz-Laguna et al., 2014), in a family with nonprogressive congenital lower motor neuron disorder with arthrogryposis (Oonk et al., 2014), and in a family with Charcot-Marie-Tooth disease type 2C (Landoure et al., 2010). Several functional studies have demonstrated the R269H variant leads to disease by a gain-of-function mechanism (Landoure et al., 2010; Deng et al., 2010; Auer-Grumback et al., 2010; Fecto et al., 2011). Furthermore, the R269H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the R269H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs within the ankyrin repeat domain 3 (Nilius et al., 2013) at a position that is highly conserved across species. Therefore, we interpret R269H as a pathogenic variant
GeneReviews RCV000202467 SCV000148057 pathogenic Neuromuscular Diseases 2014-04-02 no assertion criteria provided literature only
GeneReviews RCV000192243 SCV000239891 pathogenic Charcot-Marie-Tooth disease 2015-04-30 no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000005292 SCV000787763 pathogenic Distal spinal muscular atrophy, congenital nonprogressive 2018-04-25 no assertion criteria provided clinical testing
Invitae RCV000005293 SCV000253931 pathogenic Charcot-Marie-Tooth disease type 2C 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 269 of the TRPV4 protein (p.Arg269His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with a range of neurological disorders including scapuloperoneal spinal muscular atrophy and CMT, and it has been reported to segregate with disease in 3 independent families (PMID: 20037587, 24575025, 24789864, 20460441). ClinVar contains an entry for this variant (Variation ID: 5000). Experimental studies have shown that this missense change destabilizes protein structure, causes abnormal cellular localization, impacts channel activity, and is associated with increased cell death (PMID: 25256292, 20037586, 20037588, 21454511, 21288981). Furthermore, a different missense substitution at this codon (p.Arg269Cys) is reported to be deleterious (PMID: 21336783, 25900305, 26110311). This indicates that the arginine residue is important for TRPV4 protein function. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000005293 SCV000590830 likely pathogenic Charcot-Marie-Tooth disease type 2C 2016-06-23 criteria provided, single submitter clinical testing
OMIM RCV000005292 SCV000025470 pathogenic Distal spinal muscular atrophy, congenital nonprogressive 2011-03-08 no assertion criteria provided literature only
OMIM RCV000005293 SCV000025471 pathogenic Charcot-Marie-Tooth disease type 2C 2011-03-08 no assertion criteria provided literature only

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