12-109800659-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_021625.5(TRPV4):c.812G>A(p.Arg271His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
TRPV4
NM_021625.5 missense
NM_021625.5 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 0.934
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_benign. Variant got -4 ACMG points.
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.32012817).
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRPV4 | NM_021625.5 | c.812G>A | p.Arg271His | missense_variant | 5/16 | ENST00000261740.7 | NP_067638.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TRPV4 | ENST00000261740.7 | c.812G>A | p.Arg271His | missense_variant | 5/16 | 1 | NM_021625.5 | ENSP00000261740.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251258Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135880
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727220
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GnomAD4 genome 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74386
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 09, 2023 | 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.Arg271 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21964574). 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) 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: 882712). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 30373780). This variant is present in population databases (rs387907219, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 271 of the TRPV4 protein (p.Arg271His). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 30, 2021 | The p.R271H variant (also known as c.812G>A), located in coding exon 4 of the TRPV4 gene, results from a G to A substitution at nucleotide position 812. The arginine at codon 271 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual with a Charcot-Marie-Tooth type 1 phenotype, who also had variants in other inherited neuropathy genes; however, clinical data was limited, and functional analysis was not performed on any identified alteration (Bacquet J et al. BMJ Open, 2018 10;8:e021632). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Neuronopathy, distal hereditary motor, autosomal dominant 8 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Scapuloperoneal spinal muscular atrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Brachyrachia (short spine dysplasia) Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Spondylometaphyseal dysplasia, Kozlowski type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Metatropic dysplasia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
.;D;T;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;P;B
Vest4
MutPred
Gain of catalytic residue at F273 (P = 5e-04);Gain of catalytic residue at F273 (P = 5e-04);Gain of catalytic residue at F273 (P = 5e-04);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at