rs387906903

Positions:

• chr12-109803113-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_021625.5(TRPV4):​c.590A>G​(p.Lys197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity TRPV4_HUMAN
• 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, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.590A>G	p.Lys197Arg	missense_variant	4/16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.590A>G	p.Lys197Arg	missense_variant	4/16	1	NM_021625.5	ENSP00000261740	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

Metatropic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2010

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect TRPV4 protein function (PMID: 22702953). This variant has been observed in individual(s) with metatropic dysplasia (PMID: 20425821). ClinVar contains an entry for this variant (Variation ID: 30471). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 197 of the TRPV4 protein (p.Lys197Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -

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	0.76
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D
Polyphen		0.99	D;D;P;B;D;D
Vest4		0.89
MutPred		0.69		Gain of catalytic residue at L195 (P = 5e-04);Gain of catalytic residue at L195 (P = 5e-04);Gain of catalytic residue at L195 (P = 5e-04);Gain of catalytic residue at L195 (P = 5e-04);Gain of catalytic residue at L195 (P = 5e-04);.;
MVP		0.97
MPC		0.99
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.82

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: rs387906903; hg19: chr12-110240918;