12-109792396-C-T

Variant names:

• chr12-109792396-C-T
• rs121912633
• NM_021625.5:c.1858G>A
• TRPV4 p.Val620Ile

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

The NM_021625.5(TRPV4):​c.1858G>A​(p.Val620Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000646246: Experimental studies have shown that this missense change affects TRPV4 function (PMID:18587396, 20037588, 21573172).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V620F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 7.48
• Publications: 34 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, ClinGen, G2P
• neuromuscular disease

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

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• 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: SCV000646246: Experimental studies have shown that this missense change affects TRPV4 function (PMID: 18587396, 20037588, 21573172).
• PM1: In a hotspot region, there are 4 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, 0.822
• PP5: Variant 12-109792396-C-T is Pathogenic according to our data. Variant chr12-109792396-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1858G>A	p.Val620Ile	missense	Exon 12 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.1756G>A	p.Val586Ile	missense	Exon 12 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.1717G>A	p.Val573Ile	missense	Exon 10 of 14	NP_001170899.1	Q9HBA0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.1858G>A	p.Val620Ile	missense	Exon 12 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.1858G>A	p.Val620Ile	missense	Exon 11 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.1756G>A	p.Val586Ile	missense	Exon 12 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Brachyrachia (short spine dysplasia) (1)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth disease axonal type 2C (1)
1	-	-	Metatropic dysplasia (1)
-	-	-	Neuromuscular disease;C0410528:Skeletal dysplasia (1)
-	-	-	Skeletal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.94	N
REVEL	Pathogenic	0.81
Sift	Benign	0.041	D
Sift4G	Uncertain	0.044	D
Varity_R		0.17
gMVP		0.65
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121912633; hg19: chr12-110230201; COSMIC: COSV55680649;