rs387906905
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP5_Moderate
The NM_021625.5(TRPV4):c.947G>T(p.Arg316Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely 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
2
10
7
Clinical Significance
Conservation
PhyloP100: 4.44
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 Likely_pathogenic. Variant got 7 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). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. GenCC has associacion of the 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.
PP5
Variant 12-109798819-C-A is Pathogenic according to our data. Variant chr12-109798819-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1522581.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 20037587, 20037588, 21454511, 24789864). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt TRPV4 protein function. This missense change has been observed in individual(s) with clinical features of TRPV4-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 316 of the TRPV4 protein (p.Arg316Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;D;D;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
D;D;D;D;B;P
Vest4
MutPred
Gain of ubiquitination at K311 (P = 0.0414);Gain of ubiquitination at K311 (P = 0.0414);.;Gain of ubiquitination at K311 (P = 0.0414);.;.;
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
Publications
No publications associated with this variant yet.