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

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Athena Diagnostics Inc	RCV000005293	SCV000255846	pathogenic	Charcot-Marie-Tooth disease type 2C	2015-09-21	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
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
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
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
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
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