rs267607146

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM2PM5PP2PP5_Very_StrongBP4

The NM_021625.5(TRPV4):c.805C>T(p.Arg269Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:1

Conservation

PhyloP100: 1.03

Variant links:

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]

TRPV4 links:

TRPV4 (HGNC:):

TRPV4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 chr12-109800665-C-T 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 12-109800666-G-A is Pathogenic according to our data. Variant chr12-109800666-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109800666-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38683632). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5 linkuse as main transcript	c.805C>T	p.Arg269Cys	missense_variant	5/16	ENST00000261740.7	NP_067638.3	Q9HBA0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7 linkuse as main transcript	c.805C>T	p.Arg269Cys	missense_variant	5/16	1	NM_021625.5	ENSP00000261740.2		Q9HBA0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2024	Reported previously in association with CMT2C and distal hereditary motor neuropathy with vocal cord paresis (PMID: 24789864, 20037586, 21336783); Reported in five family members, of which two were clinically affected and three were clinically unaffected, indicating reduced penetrance (PMID: 21336783); Published functional studies show that R269C alters the channel activity and leads to increased rate of cell death (PMID: 20037586); 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: 20460441, 35170874, 31468327, 22702953, 26110311, 24963089, 22617546, 33664271, 31041394, 33820833, 25900305, 36738734, 24789864, 21336783, 20037586, 22851605) -

Charcot-Marie-Tooth disease axonal type 2C

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 269 of the TRPV4 protein (p.Arg269Cys). This variant is present in population databases (rs267607146, gnomAD 0.01%). This missense change has been observed in individual(s) with TRPV4-related neuropathy (PMID: 20037586, 21336783, 24789864, 25900305, 26110311). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5002). 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. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037586, 22702953). 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: 20037587, 20037588, 24575025, 24963089, 26948711, 27751652). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The p.R269C pathogenic mutation (also known as c.805C>T), located in coding exon 4 of the TRPV4 gene, results from a C to T substitution at nucleotide position 805. The arginine at codon 269 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported to be de novo in individuals with skeletal dysplasia and scapuloperoneal spinal muscular atrophy (SPSMA) and distal hereditary motor neuropathy (dHMN) (Evangelista et al. Neuromuscul Disord, 2015 Jun;25:516-21; Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26). In addition, this variant was identified in multiple unrelated individuals with TRPV-related disease (Deng S et al. Neuromolecular Med, 2020 Mar;22:68-72; Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26; Berciano et al. J Neurol. 2011 Aug;258:1413-21). Functional studies indicate that this alteration impairs normal channel activity, mitochondrial transport in axons, and neuronal projections in Drosophila and increases cytotoxicity in vitro (Woolums et al. Nat Commun, 2020 May 29;11:2679; Velilla et al. Neurol Genet, 2019 Mar 7;5:e312.). Another alteration at the same codon, p.R269H (c.806 G>A), has been detected in individuals with Charcot-Marie-Tooth disease (CMT), scapuloperoneal spinal muscular atrophy (SPSMA), congenital distal spinal muscular atrophy (CDSMA) and arthrogryposis, with some functional evidence (Landoure et al. Nat Genet, 2010 Feb;42:170-4; Auer-Grumbach et al. Nat Genet, 2010 Feb;42:160-4; Deng et al. Nat Genet. 2010 Feb;42:165-9.). This amino acid position is well conserved in available vertebrate species; however, cysteine is the reference amino acid in other vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neuronopathy, distal hereditary motor, autosomal dominant 8

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Hereditary motor neuron disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

- -

Scapuloperoneal spinal muscular atrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Distal spinal muscular atrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Neuromuscular disease

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

0.061

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

-0.095

N;N;N;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.96

N;N;N;N

REVEL

Uncertain

0.64

Sift

Benign

0.30

T;T;T;T

Sift4G

Uncertain

0.055

T;T;T;T

Polyphen

1.0

D;D;D;B

Vest4

0.80

MutPred

0.80

Gain of catalytic residue at R271 (P = 0.0185);Gain of catalytic residue at R271 (P = 0.0185);Gain of catalytic residue at R271 (P = 0.0185);.;

MVP

0.95

MPC

1.4

ClinPred

0.97

GERP RS

4.9

Varity_R

0.60

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over