rs387906904

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_021625.5(TRPV4):c.694C>T(p.Arg232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (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: 1.37

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the TRPV4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 1.9225 (below the threshold of 3.09). Trascript score misZ: 3.5609 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

PP5

Variant 12-109803009-G-A is Pathogenic according to our data. Variant chr12-109803009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109803009-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5 link	c.694C>T	p.Arg232Cys	missense_variant	Exon 4 of 16	ENST00000261740.7	NP_067638.3	Q9HBA0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7 link	c.694C>T	p.Arg232Cys	missense_variant	Exon 4 of 16	1	NM_021625.5	ENSP00000261740.2		Q9HBA0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727164

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

Cov.:

ClinVar

Significance: Pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2C

Pathogenic:4

Jan 31, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21288981, 21288981). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030472 / PMID: 20460441). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 20460441, 21288981, 24789864). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20460441, 21288981, 24789864). Different missense changes at the same codon (p.Arg232Pro, p.Arg232Ser) have been reported to be associated with TRPV4 related disorder (ClinVar ID: VCV001493962 / PMID: 24789864). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant p.Arg232Cys variant in the TRPV4 gene has been observed in several individuals with TRPV4-related disorders, including distal hereditary motor neuropathy type VIII (dHMN8), scapuloperoneal spinal muscular atrophy (SPSMA), and Charcot-Marie-Tooth disease type 2C (CMT2C). This variant is not present in population databases (GnomAD and ABraOM). ClinVar classifies this variant as Pathogenic (Variation ID: 30472), 2 stars (multiple consistent, 9 submissions), backed by functional studies (requires user validation) mentioned in 21288981, and also citing 8 articles (26948711, 26048687, 24789864, 22702953, 22526352 and 3 more). This variant replaces arginine with cysteine at codon 232 of the TRPV4 protein, which is highly conserved across different species. In summary, the p.Arg232Cys meets our criteria to be classified as pathogenic. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 232 of the TRPV4 protein (p.Arg232Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 2C, distal hereditary motor neuropathy, and/or scapuloperoneal spinal muscular atrophy (PMID: 20460441, 21288981, 22526352, 24789864, 26048687). 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: 30472). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 21288981, 22702953). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Jun 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect impacting ATP binding and subcellular localization (Klein et al., 2011; Inada et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26048687, 25256292, 31827005, 34758253, 20460441, 21288981, 22526352, 33664271, 32376792, 22702953, 24789864) -

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/251028 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. One de novo case without parental identity confirmed. -

Charcot-Marie-Tooth disease

Pathogenic:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal dominant 8

Pathogenic:1

Jan 31, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Spondylometaphyseal dysplasia, Kozlowski type

Pathogenic:1

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal dominant

Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuromuscular disease;C0410528:Skeletal dysplasia

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;.;.;.

Eigen

Benign

0.093

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.97

.;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.4

M;M;M;M;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.014

D;D;T;D;T;D

Sift4G

Uncertain

0.019

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.89

MutPred

0.58

Gain of catalytic residue at I234 (P = 0);Gain of catalytic residue at I234 (P = 0);Gain of catalytic residue at I234 (P = 0);Gain of catalytic residue at I234 (P = 0);Gain of catalytic residue at I234 (P = 0);.;

MVP

0.95

MPC

1.3

ClinPred

0.91

GERP RS

2.6

Varity_R

0.49

gMVP

0.86

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