rs267607145
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_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 Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TRPV4
NM_021625.5 missense
NM_021625.5 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 3.03
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
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 Lovd as [Pathogenic].
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, 0.785
PP5
Variant 12-109798820-G-A is Pathogenic according to our data. Variant chr12-109798820-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRPV4 | NM_021625.5 | c.946C>T | p.Arg316Cys | missense_variant | 6/16 | ENST00000261740.7 | NP_067638.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TRPV4 | ENST00000261740.7 | c.946C>T | p.Arg316Cys | missense_variant | 6/16 | 1 | NM_021625.5 | ENSP00000261740.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2022 | For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037587, 21454511). 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. ClinVar contains an entry for this variant (Variation ID: 5001). 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. This variant is not present in population databases (gnomAD no frequency). 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). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2010 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | TRPV4: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | 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) - |
TRPV4-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 12, 2021 | 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. - |
Charcot-Marie-Tooth disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2021 | 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
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2010 | - - |
Neuronopathy, distal hereditary motor, autosomal dominant Uncertain:1
| Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Neuromuscular disease Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.;L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;N;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;D;D;D;D;D
Vest4
MutPred
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
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at