rs267607144

Variant names:

• chr12-109800665-C-T
• rs267607144
• NM_021625.5:c.806G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-109800665-C-T
• chr12-109800665-C-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3 PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_021625.5(TRPV4):​c.806G>A​(p.Arg269His) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000253931: Experimental studies have shown that this missense change affects TRPV4 function (PMID:20037586, 20037588, 21288981, 21454511, 25256292)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1 O:1
• Conservation: PhyloP100: 3.08
• Publications: 37 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, ClinGen
• neuromuscular disease

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, 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), Genomics England PanelApp, Orphanet
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• brachyolmia

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• spondyloepimetaphyseal dysplasia, Maroteaux type

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000253931: Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037586, 20037588, 21288981, 21454511, 25256292).; SCV002059021: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20037586, 20037587, 20037588, 21288981, 21454511, 25256292).; SCV000293511: Several published functional studies have demonstrated the R269H variant leads to disease by a gain-of-function mechanism (PMID: 20037586, 20037587, 20037588, 21454511); SCV004800957: "In vitro functional studies provide some evidence that the p.Arg269His variant may impact protein function." PMID:21454511, PMID:21288981, PMID:20037588, PMID:20037586
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109800666-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 12-109800665-C-T is Pathogenic according to our data. Variant chr12-109800665-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33595973). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021625.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.806G>A	p.Arg269His	missense	Exon 5 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.704G>A	p.Arg235His	missense	Exon 5 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_147204.2		c.806G>A	p.Arg269His	missense	Exon 4 of 14	NP_671737.1	Q9HBA0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.806G>A	p.Arg269His	missense	Exon 5 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.806G>A	p.Arg269His	missense	Exon 4 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.704G>A	p.Arg235His	missense	Exon 5 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000287 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Charcot-Marie-Tooth disease axonal type 2C (6)
2	1	-	Neuronopathy, distal hereditary motor, autosomal dominant 8 (3)
3	-	-	not provided (3)
2	-	-	TRPV4-related bone disorder (2)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Spondylometaphyseal dysplasia, Kozlowski type;C0265281:Metatropic dysplasia;C0432227:Brachyrachia (short spine dysplasia);C0751335:Scapuloperoneal spinal muscular atrophy;C1838492:Neuronopathy, distal hereditary motor, autosomal dominant 8;C1847406:Familial digital arthropathy-brachydactyly;C1853710:Charcot-Marie-Tooth disease axonal type 2C;C1868616:Parastremmatic dwarfism;C3150755:Sodium serum level quantitative trait locus 1;C3159322:Spondyloepimetaphyseal dysplasia, Maroteaux type;C4479260:Avascular necrosis of femoral head, primary, 2 (1)
-	-	-	Neuromuscular disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.46	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.64	N
REVEL	Uncertain	0.57
Sift	Benign	0.26	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.75		Gain of catalytic residue at F273 (P = 0.012)
MVP		0.94
MPC		1.2
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.68
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607144; hg19: chr12-110238470; COSMIC: COSV55686649;