Submissions for variant NM_021625.5(TRPV4):c.806G>A (p.Arg269His)

dbSNP: rs267607144

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000005293	SCV000253931	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2022-10-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg269 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21336783, 25900305, 26110311). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037586, 20037588, 21288981, 21454511, 25256292). 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) performed at Invitae indicates that this missense variant is expected to disrupt TRPV4 protein function. ClinVar contains an entry for this variant (Variation ID: 5000). This missense change has been observed in individuals with a range of neurological disorders including scapuloperoneal spinal muscular atrophy and CMT (PMID: 20037587, 20460441, 24575025, 24789864). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the TRPV4 protein (p.Arg269His).
Athena Diagnostics	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 Children's Health, Delaware	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); Familial digital arthropathy-brachydactyly; Metatropic dysplasia; Parastremmatic dwarfism; Spondylometaphyseal dysplasia, Kozlowski type; Spondyloepimetaphyseal dysplasia, Maroteaux type; Neuronopathy, distal hereditary motor, autosomal dominant 8; 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 Center for Human Genetics 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
3billion	RCV000005292	SCV002059021	pathogenic	Neuronopathy, distal hereditary motor, autosomal dominant 8	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005000, PMID:20037586, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20037587, 25256292, 20037588, 21454511, 21288981, 20037586, PS3_S). A different missense change at the same codon has been reported to be associated with TRPV4 related disorder (ClinVar ID: VCV000005002, PMID:20037586, PM5_P). A missense variant is a common mechanism associated with Neuronopathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 24789864, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000005293	SCV003836441	pathogenic	Charcot-Marie-Tooth disease axonal type 2C	2022-04-17	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV003320352	SCV004024495	pathogenic	TRPV4-related bone disorder	2023-07-01	criteria provided, single submitter	research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003320352	SCV004800957	pathogenic	TRPV4-related bone disorder	2024-03-12	criteria provided, single submitter	curation	The heterozygous p.Arg269His variant in TRPV4 was identified by our study in one individual whose features included congenital fibrosis of the extraocular muscles of the right eye, abducens palsy of the left eye, motor axonal neuropathy, and arthrogryposis, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for TRPV4-related disease The p.Arg269His variant in TRPV4 has been previously reported in over 10 unrelated individuals with autosomal dominant TRPV4-related disease (PMID: 20037586, PMID: 27751652, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025, PMID: 24789864) and segregated with disease in 59 affected relatives from 7 families (PMID: 20037586, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in at least two unrelated individuals with confirmed maternity and paternity (PMID: 24789864, PMID: 30230566). This variant has also been reported in ClinVar (Variation ID: 5000) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg269His variant may impact protein function (PMID: 21454511, PMID: 21288981, PMID: 20037588, PMID: 20037586). However, these types of assays may not accurately represent biological function. 2 additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg269Ser and p.Arg269Cys, have been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 20037586, 21336783, 24789864, 25900305, 26110311; Variation ID: 536867, 5002). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein.In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant TRPV4-related disease. ACMG/AMP Criteria applied: PS2_Moderate, PS3, PS4, PM2_Supporting, PM5_Supporting, PP1_strong (Richards 2015).
OMIM	RCV000005292	SCV000025470	pathogenic	Neuronopathy, distal hereditary motor, autosomal dominant 8	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	not provided	Neuromuscular disease		no assertion provided	literature only
Institute of Human Genetics, Cologne University	RCV000005292	SCV000787763	pathogenic	Neuronopathy, distal hereditary motor, autosomal dominant 8	2018-04-25	no assertion criteria provided	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000005292	SCV001167535	uncertain significance	Neuronopathy, distal hereditary motor, autosomal dominant 8		no assertion criteria provided	research