rs267607148

chr12-109800639-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

The NM_021625.5(TRPV4):c.832G>A(p.Glu278Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E278D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.58

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPV4
• PP5: Variant 12-109800639-C-T is Pathogenic according to our data. Variant chr12-109800639-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32223833).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.832G>A	p.Glu278Lys	missense_variant	5/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.832G>A	p.Glu278Lys	missense_variant	5/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 22702953). 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. ClinVar contains an entry for this variant (Variation ID: 18434). This missense change has been observed in individuals with spondylometaphyseal dysplasia and skeletal dysplasia with peripheral neuropathy (PMID: 20577006, 22419508). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 278 of the TRPV4 protein (p.Glu278Lys). -

Spondylometaphyseal dysplasia, Kozlowski type 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	Benign	0.29
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Benign	0.095
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.41	N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.28	N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.64	T;T;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.96	D;D;D;B
Vest4		0.82
MutPred		0.42		Gain of ubiquitination at E278 (P = 0.0198);Gain of ubiquitination at E278 (P = 0.0198);Gain of ubiquitination at E278 (P = 0.0198);.;
MVP		0.90
MPC		0.66
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.57
gMVP		0.69

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: rs267607148; hg19: chr12-110238444;