rs77975504

chr12-109792695-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_021625.5(TRPV4):c.1781G>A(p.Arg594His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R594C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 7.91

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_021625.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109792696-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1484191.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TRPV4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 12-109792695-C-T is Pathogenic according to our data. Variant chr12-109792695-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109792695-C-T is described in Lovd as [Pathogenic]. Variant chr12-109792695-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.1781G>A	p.Arg594His	missense_variant	11/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.1781G>A	p.Arg594His	missense_variant	11/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylometaphyseal dysplasia, Kozlowski type Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004994). Different missense changes at the same codon (p.Arg594Cys, p.Arg594Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001224354 , VCV001484191). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PM1, PM2, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 02, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	May 06, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 27, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The c.1781G>A (p.R594H) alteration is located in exon 11 (coding exon 10) of the TRPV4 gene. This alteration results from a G to A substitution at nucleotide position 1781, causing the arginine (R) at amino acid position 594 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with Kozlowski type spondylometaphyseal dysplasia and metatropic dysplasia, including some cases of reported de novo occurrence (Krakow, 2009; Dai, 2010; Andreucci, 2011; Zhang, 2015; Bieganski, 2017; Hsu, 2019). Another alteration at the same codon, c.1780C>A (p.R594S), has been described in an individual with metatropic dysplasia (Andreucci, 2011). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R594H alteration altered basal calcium channel activity in vitro (Krakow, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease axonal type 2C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 594 of the TRPV4 protein (p.Arg594His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spondylometaphyseal dysplasia, Kozlowski type as well as other related skeletal dysplasias (PMID: 19232556, 20503319, 20577006, 21658220). ClinVar contains an entry for this variant (Variation ID: 4994). 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) has been performed at Invitae 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: 19232556, 21573172). For these reasons, this variant has been classified as Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 30, 2021

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP3 supporting -

Parastremmatic dwarfism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Metatropic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Neuromuscular disease;C0410528:Skeletal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.5	H;H;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.91
MutPred		0.80		Gain of catalytic residue at L596 (P = 2e-04);Gain of catalytic residue at L596 (P = 2e-04);.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.72
gMVP		0.88

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: rs77975504; hg19: chr12-110230500; COSMIC: COSV55680868;