Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000005293 | SCV000253931 | pathogenic | Charcot-Marie-Tooth disease axonal type 2C | 2019-10-03 | 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. |
Athena Diagnostics Inc | RCV000005293 | SCV000255846 | pathogenic | Charcot-Marie-Tooth disease axonal type 2C | 2015-09-21 | criteria provided, single submitter | clinical testing | |
Gene |
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 |
Molecular Diagnostics Lab, |
RCV000005293 | SCV000590830 | likely pathogenic | Charcot-Marie-Tooth disease axonal type 2C | 2016-06-23 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000623703 | SCV000741621 | pathogenic | Inborn genetic diseases | 2016-06-20 | criteria provided, single submitter | clinical testing | |
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 axonal type 2C; Avascular necrosis of femoral head, primary, 2 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Molecular Genetics Laboratory, |
RCV000192243 | SCV001335961 | pathogenic | Charcot-Marie-Tooth disease | 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 axonal type 2C | 2011-03-08 | no assertion criteria provided | literature only | |
Gene |
RCV000202467 | SCV000148057 | pathogenic | Neuromuscular disease | 2014-04-02 | no assertion criteria provided | literature only | |
Gene |
RCV000192243 | SCV000239891 | pathogenic | Charcot-Marie-Tooth disease | 2015-04-30 | no assertion criteria provided | literature only | |
Institute of Human Genetics, |
RCV000005292 | SCV000787763 | pathogenic | Distal spinal muscular atrophy, congenital nonprogressive | 2018-04-25 | no assertion criteria provided | clinical testing | |
Lupski Lab, |
RCV000005292 | SCV001167535 | uncertain significance | Distal spinal muscular atrophy, congenital nonprogressive | no assertion criteria provided | research |