rs267607144

Positions:

• chr12-109800665-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM2 PM5 PP2 PP5_Very_Strong BP4

The NM_021625.5(TRPV4):​c.806G>A​(p.Arg269His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1 O:1
• Conservation: PhyloP100: 3.08

Genes affected

TRPV4 (HGNC:18083): (transient receptor potential cation channel subfamily V member 4) This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109800666-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPV4. . Gene score misZ 1.9225 (greater than the threshold 3.09). Trascript score misZ 3.5609 (greater than threshold 3.09). GenCC has associacion of gene with TRPV4-related bone disorder, metatropic dysplasia, Charcot-Marie-Tooth disease axonal type 2C, spondylometaphyseal dysplasia, Kozlowski type, familial avascular necrosis of femoral head, parastremmatic dwarfism, neuromuscular disease, autosomal dominant brachyolmia, familial digital arthropathy-brachydactyly, neuronopathy, distal hereditary motor, autosomal dominant 8, scapuloperoneal spinal muscular atrophy, autosomal dominant.
• PP5: Variant 12-109800665-C-T is Pathogenic according to our data. Variant chr12-109800665-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109800665-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33595973). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.806G>A	p.Arg269His	missense_variant	5/16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.806G>A	p.Arg269His	missense_variant	5/16	1	NM_021625.5	ENSP00000261740	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2C Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 08, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 17, 2022	- -

Neuronopathy, distal hereditary motor, autosomal dominant 8 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 08, 2011	- -
Uncertain significance, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2019	PS3, PS4_moderate, PM1, PM2, PM6, PP1, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	Several published functional studies have demonstrated the R269H variant leads to disease by a gain-of-function mechanism (PMID: 20037586, 20037587, 20037588, 21454511); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22702953, 21454511, 33060286, 31468327, 24963089, 24575025, 20037587, 20037588, 23306656, 26948711, 27751652, 30373780, 30230566, 29858556, 31230720, 32400062, 37366078, 36964972, 24789864, 20037586, 21336783) -

TRPV4-related bone disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 12, 2024	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). -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2016

- -

Spondylometaphyseal dysplasia, Kozlowski type;C0265281:Metatropic dysplasia;C0432227:Brachyrachia (short spine dysplasia);C0751335:Scapuloperoneal spinal muscular atrophy;C1838492:Neuronopathy, distal hereditary motor, autosomal dominant 8;C1847406:Familial digital arthropathy-brachydactyly;C1853710:Charcot-Marie-Tooth disease axonal type 2C;C1868616:Parastremmatic dwarfism;C3150755:Sodium serum level quantitative trait locus 1;C3159322:Spondyloepimetaphyseal dysplasia, Maroteaux type;C4479260:Avascular necrosis of femoral head, primary, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Neuromuscular disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	.;D;D;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.46	N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.64	N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;D;D;B
Vest4		0.78
MutPred		0.75		Gain of catalytic residue at F273 (P = 0.012);Gain of catalytic residue at F273 (P = 0.012);Gain of catalytic residue at F273 (P = 0.012);.;
MVP		0.94
MPC		1.2
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607144; hg19: chr12-110238470; COSMIC: COSV55686649;