12-109798823-G-A

Position:

chr12-109798823-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_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 (★★).

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:13U:1O:1

Conservation

PhyloP100: 4.42

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 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

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 [Likely_pathogenic]. Clinvar id is 4999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109798823-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5 linkuse as main transcript	c.943C>T	p.Arg315Trp	missense_variant	6/16	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.943C>T	p.Arg315Trp	missense_variant	6/16	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

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:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain: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	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 17, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	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, 35170874, 36118854, 37706131, 20037588, 33664271) -

Charcot-Marie-Tooth disease axonal type 2C

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2013	- -

Scapuloperoneal spinal muscular atrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -

TRPV4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2022

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

TRPV4-Associated Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

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

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Neuromuscular disease

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

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

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;.;.

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

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