rs387906324

Variant names:

• chr12-109808308-C-T
• rs387906324
• NM_021625.5:c.547G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_021625.5(TRPV4):​c.547G>A​(p.Glu183Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E183E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.67

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 Uncertain_significance. Variant got 5 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.
• PP5: Variant 12-109808308-C-T is Pathogenic according to our data. Variant chr12-109808308-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18437.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.547G>A	p.Glu183Lys	missense_variant	Exon 3 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.547G>A	p.Glu183Lys	missense_variant	Exon 3 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 183 of the TRPV4 protein (p.Glu183Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TRPV4-related conditions (PMID: 20503319; Invitae). ClinVar contains an entry for this variant (Variation ID: 18437). 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: 22702953). This variant disrupts the p.Gly183 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been observed in individuals with TRPV4-related conditions (PMID: 20503319, 25802885; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Spondyloepimetaphyseal dysplasia, Maroteaux type Pathogenic:1

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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	0.68
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.025
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	.;D;D;T;D;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.9	L;L;L;L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.93	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.24	T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.031	B;B;B;B;B;B
Vest4		0.86
MutPred		0.44		Loss of ubiquitination at K178 (P = 0.0193);Loss of ubiquitination at K178 (P = 0.0193);Loss of ubiquitination at K178 (P = 0.0193);Loss of ubiquitination at K178 (P = 0.0193);Loss of ubiquitination at K178 (P = 0.0193);.;
MVP		0.92
MPC		0.49
ClinPred		0.73	D
GERP RS		3.7
Varity_R		0.53
gMVP		0.67

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: rs387906324; hg19: chr12-110246113;