12-109798823-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_021625.5(TRPV4):c.943C>T(p.Arg315Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,018 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315Q) has been classified as Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1O:1

Conservation

PhyloP100: 4.42

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

metatropic dysplasia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
neuromuscular disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spondylometaphyseal dysplasia, Kozlowski type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
TRPV4-related bone disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
autosomal dominant brachyolmia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
Charcot-Marie-Tooth disease axonal type 2C
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
scapuloperoneal spinal muscular atrophy, autosomal dominant
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
familial avascular necrosis of femoral head
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial digital arthropathy-brachydactyly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neuronopathy, distal hereditary motor, autosomal dominant 8
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
parastremmatic dwarfism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRPV4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_021625.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-109798822-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 422303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 12-109798823-G-A is Pathogenic according to our data. Variant chr12-109798823-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5 link	c.943C>T	p.Arg315Trp	missense_variant	Exon 6 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.943C>T	p.Arg315Trp	missense_variant	Exon 6 of 16	1	NM_021625.5	ENSP00000261740.2		Q9HBA0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

1461830

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Oct 17, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 15, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest significant disruption of TRPV4-RhoA interaction as well as suppressed interaction of wild-type TRPV4 with RhoA (PMID: 33664271); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21115951, 21454511, 22702953, 31191204, 31041394, 24830047, 32579787, 34426522, 32481620, 35032046, 36118854, 20037588, 33664271, 35170874, 37706131) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2C

Pathogenic:3

Dec 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 24, 2013

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2024

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 tryptophan, which is neutral and slightly polar, at codon 315 of the TRPV4 protein (p.Arg315Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor and sensory neuropathy type 2C (HMSN2C), scapuloperoneal spinal muscular atrophy (SPSMA), Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis, and congenital distal SMA (PMID: 20037588, 20460441, 21115951, 22065612). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4999). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037588, 21454511, 22702953). For these reasons, this variant has been classified as Pathogenic. -

Scapuloperoneal spinal muscular atrophy

Pathogenic:2

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

TRPV4-related disorder

Pathogenic:1

Jan 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TRPV4 c.943C>T variant is predicted to result in the amino acid substitution p.Arg315Trp. This variant has been reported in multiple individuals with TRPV4-related autosomal dominant conditions, including scapuloperoneal spinal muscular atrophy, and functional studies support its pathogenicity (Auer-Grumbach et al. 2010. PubMed ID: 20037588; Fecto et al. 2011. PubMed ID: 21454511; Inada et al. 2012. PubMed ID: 22702953). It has been reported as a de novo finding, and also to segregate with affected status in families (Faye et al. 2019. PubMed ID: 31191204; Chen et al. 2010. PubMed ID: 21115951; ClinVar Variation ID: 4999). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 04, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.943C>T (p.R315W) alteration is located in exon 6 (coding exon 5) of the TRPV4 gene. This alteration results from a C to T substitution at nucleotide position 943, causing the arginine (R) at amino acid position 315 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected as de novo in an individual with Kozslowski type spondylometaphyseal dysplasia and Charcot-Marie-Tooth disease type 2C (CMT2C) (Faye, 2019). It has also been found to segregate with TRPV4-related disorders such as congenital distal spinal muscular atrophy (CDSMA), scapuloperoneal spinal muscular atrophy (SPSMA), and hereditary motor and sensory neuropathy type IIc (HMSN2C) in multiple families (Chen, 2010; Auer-Grumbach, 2010). This alteration has been described in additional unrelated individuals with TRPV4-related disorders (Tunca, 2020; Velilla, 2019; Aharoni, 2011; Echaniz-Laguna, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

Neuronopathy, distal hereditary motor, autosomal dominant 8

Pathogenic:1

Dec 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Scapuloperoneal spinal muscular atrophy;C1838492:Neuronopathy, distal hereditary motor, autosomal dominant 8

Pathogenic:1

Sep 21, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2- PM1- PP3- PP5 -

TRPV4-Associated Disorders

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as a heterozygous change in families with hereditary motor and sensory neuropathy type 2C, scapuloperoneal spinal muscular atrophy, Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis and congenital distal SMA (PMID: 20037588, 21115951, 20460441, 22065612). Functional studies show that this variant alters the localization of the TRPV4 protein to the cell surface and increases the basal calcium levels leading to increased cell death (PMID: 20037588, 22702953, 21454511). The c.943C>T (p.Arg315Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.943C>T (p.Arg315Trp) variant is classified as Pathogenic. -

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

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

Benign

0.33

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;D;.;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

.;D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D

MetaSVM

Uncertain

0.046

MutationAssessor

Benign

2.0

M;M;.;M;.;.

PhyloP100

4.4

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.012

D;D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.92

MutPred

0.71

Gain of catalytic residue at R316 (P = 3e-04);Gain of catalytic residue at R316 (P = 3e-04);.;Gain of catalytic residue at R316 (P = 3e-04);.;.;

MVP

0.90

MPC

1.2

ClinPred

0.96

GERP RS

2.4

Varity_R

0.32

gMVP

0.77

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over