rs515726162

Variant names:

• chr12-109792403-G-T
• rs515726162
• NM_021625.5:c.1851C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_021625.5(TRPV4):​c.1851C>A​(p.Phe617Leu) variant causes a missense change. 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.51
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• metatropic dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• TRPV4-related bone disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• autosomal dominant brachyolmia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial avascular necrosis of femoral head

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial digital arthropathy-brachydactyly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, autosomal dominant 8

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parastremmatic dwarfism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_021625.5 (TRPV4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 12-109792403-G-T is Pathogenic according to our data. Variant chr12-109792403-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.1851C>A	p.Phe617Leu	missense_variant	Exon 12 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.1851C>A	p.Phe617Leu	missense_variant	Exon 12 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 617 of the TRPV4 protein (p.Phe617Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metatropic dysplasia (PMID: 20425821, 24342753, 26377240). ClinVar contains an entry for this variant (Variation ID: 126472). 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: 21573172). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 03, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondylometaphyseal dysplasia, Kozlowski type Pathogenic:1

Dec 13, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PM1, PM2, PP3, PP5 - Same amino acid change as a known pathogenic variant. Low frequency in gnomAD population databases. This variant has been previously reported as causative for metatropic dysplasia. (PMID:20425821). -

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	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.6	H;H;.;.;.;.
PhyloP100		4.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.97
MutPred		0.75		Gain of catalytic residue at Y621 (P = 0.0154);Gain of catalytic residue at Y621 (P = 0.0154);.;.;.;.;
MVP		0.96
MPC		2.2
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs515726162; hg19: chr12-110230208; COSMIC: COSV55685161;