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

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000005293	SCV000253931	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2020-10-08	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
GeneDx	RCV000235740	SCV000293511	pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing	Several published 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); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 24789864, 32400062, 31230720, 29858556, 30230566, 30373780, 27751652, 26948711, 21454511, 22702953, 31468327, 23306656, 20037588, 20037587, 24575025, 24963089, 20037586)
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children	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,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,London Health Sciences Centre	RCV000192243	SCV001335961	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000235740	SCV001501438	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235740	SCV001714417	pathogenic	not provided	2019-04-27	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM1, PM2, PM6, PP1, PP5
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
GeneReviews	RCV000202467	SCV000148057	pathogenic	Neuromuscular disease	2014-04-02	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
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000005292	SCV001167535	uncertain significance	Distal spinal muscular atrophy, congenital nonprogressive		no assertion criteria provided	research