rs267607145

Variant names:

• chr12-109798820-G-A
• rs267607145
• NM_021625.5:c.946C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109798820-G-A
• chr12-109798820-G-C
• chr12-109798820-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_021625.5(TRPV4):​c.946C>T​(p.Arg316Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R316H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1 O:1
• Conservation: PhyloP100: 3.03
• Publications: 28 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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr12-109798819-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• PP5: Variant 12-109798820-G-A is Pathogenic according to our data. Variant chr12-109798820-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5001.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.946C>T	p.Arg316Cys	missense_variant	Exon 6 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.946C>T	p.Arg316Cys	missense_variant	Exon 6 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Arg316 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21288981, 24319099, 24789864). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy 2C (HMSN2C) (PMID: 20037587, 20037588, 24789864). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5001). 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: 20037587, 21454511). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 316 of the TRPV4 protein (p.Arg316Cys). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPV4: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

Jun 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; the R316C variant results in increased calcium channel activity suggestive of a gain of function effect (Deng et al., 2010; Fecto et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20037588, 22702953, 21454511, 24789864, 32376792, 31468327, 20037587) -

Charcot-Marie-Tooth disease Pathogenic:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRPV4-related disorder Pathogenic:1

May 12, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TRPV4 c.946C>T (p.Arg316Cys) variant is a missense variant that has been reported in a heterozygous state in at least six unrelated individuals with scapuloperoneal spinal muscular atrophy, hereditary motor and sensory neuropathy (type 2C), or distal hereditary motor neuropathy (Deng et al. 2010; Auer-Grumbach et al. 2010; Echaniz-Laguna et al. 2014; Deng et al. 2020). The variant segregated with the disease in multiple affected family members in three of the families and was reported to occur in a de novo state in one individual. The p.Arg316Cys variant is not reported in the Genome Aggregation Database, in a region of good sequencing coverage, indicating it is rare. The variant occurs in the ankyrin repeat-containing region of the cytoplasmic N terminus where several other pathogenic missense variants have been reported. In vitro functional studies suggest it has a gain-of-function effect and increases calcium influx (Deng et al. 2010; Fecto et al. 2011). However, conflicting results have also been reported (Auer-Grumbach et al. 2010), and the pathognomonic mechanism may not yet be fully understood (Echaniz-Laguna et al. 2014). Based on the collective evidence, the p.Arg316Cys variant is classified as pathogenic for TRPV4-related disorders. -

Inborn genetic diseases Pathogenic:1

Aug 26, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R316C pathogenic mutation (also known as c.946C>T), located in coding exon 5 of the TRPV4 gene, results from a C to T substitution at nucleotide position 946. The arginine at codon 316 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported to be de novo in an individual with distal hereditary motor neuropathy (dHMN) (Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26), and it was found to segregate with scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot-Marie-Tooth disease type 2C (CMT2C) in two separate families (Landouré G et al. Nat Genet, 2010 Feb;42:170-4; Deng HX et al. Nat Genet, 2010 Feb;42:165-9). In addition, this variant was identified in multiple individuals with TRPV-related disease (Auer-Grumbach M et al. Nat Genet, 2010 Feb;42:160-4; Deng S et al. Neuromolecular Med, 2020 03;22:68-72; Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26). Functional studies show that this alteration causes abnormal channel activity, leading to cytotoxic hypercalcemia (Landouré G et al. Nat Genet, 2010 Feb;42:170-4; Auer-Grumbach M et al. Nat Genet, 2010 Feb;42:160-4; Deng S et al. Neuromolecular Med, 2020 03;22:68-72; Fecto F et al. J Biol Chem, 2011 May;286:17281-91; Klein CJ et al. Neurology, 2011 Mar;76:887-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Scapuloperoneal spinal muscular atrophy Pathogenic:1

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuronopathy, distal hereditary motor, autosomal dominant Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuromuscular disease 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	Benign	0.25
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;D;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L;L;.;L;.;.
PhyloP100		3.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D;D;D;D;N;D
REVEL	Uncertain	0.62
Sift	Benign	0.033	D;D;D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.84
MutPred		0.73		Gain of catalytic residue at M314 (P = 0);Gain of catalytic residue at M314 (P = 0);.;Gain of catalytic residue at M314 (P = 0);.;.;
MVP		0.88
MPC		1.4
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.36
gMVP		0.78
Mutation Taster		=0/100	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: rs267607145; hg19: chr12-110236625; COSMIC: COSV55681642;