12-109800665-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP2PP5_Very_StrongBP4
The NM_021625.5(TRPV4):c.806G>A(p.Arg269His) 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 benign outcome for this variant. 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. R269C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TRPV4
NM_021625.5 missense
NM_021625.5 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 3.08
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.
PM1
In a hotspot region, there are 5 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 chr12-109800666-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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.
PP5
Variant 12-109800665-C-T is Pathogenic according to our data. Variant chr12-109800665-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109800665-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.33595973). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TRPV4 | NM_021625.5 | c.806G>A | p.Arg269His | missense_variant | 5/16 | ENST00000261740.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TRPV4 | ENST00000261740.7 | c.806G>A | p.Arg269His | missense_variant | 5/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 17, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 08, 2011 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jun 23, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg269 amino acid residue in TRPV4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21336783, 25900305, 26110311). 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: 20037586, 20037588, 21288981, 21454511, 25256292). 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. ClinVar contains an entry for this variant (Variation ID: 5000). This missense change has been observed in individuals with a range of neurological disorders including scapuloperoneal spinal muscular atrophy and CMT (PMID: 20037587, 20460441, 24575025, 24789864). 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 histidine, which is basic and polar, at codon 269 of the TRPV4 protein (p.Arg269His). - |
Neuronopathy, distal hereditary motor, autosomal dominant 8 Pathogenic:3Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 25, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 08, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005000, PMID:20037586, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20037587, 25256292, 20037588, 21454511, 21288981, 20037586, PS3_S). A different missense change at the same codon has been reported to be associated with TRPV4 related disorder (ClinVar ID: VCV000005002, PMID:20037586, PM5_P). A missense variant is a common mechanism associated with Neuronopathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 24789864, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Uncertain significance, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2021 | Several published functional studies have demonstrated the R269H variant leads to disease by a gain-of-function mechanism (Landoure et al., 2010; Deng et al., 2010; Auer-Grumback et al., 2010; Fecto et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 24789864, 32400062, 31230720, 29858556, 30230566, 30373780, 27751652, 26948711, 21454511, 22702953, 31468327, 23306656, 20037588, 20037587, 24575025, 24963089, 20037586) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 27, 2019 | PS3, PS4_moderate, PM1, PM2, PM6, PP1, PP5 - |
TRPV4-related bone disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Mar 12, 2024 | The heterozygous p.Arg269His variant in TRPV4 was identified by our study in one individual whose features included congenital fibrosis of the extraocular muscles of the right eye, abducens palsy of the left eye, motor axonal neuropathy, and arthrogryposis, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for TRPV4-related disease The p.Arg269His variant in TRPV4 has been previously reported in over 10 unrelated individuals with autosomal dominant TRPV4-related disease (PMID: 20037586, PMID: 27751652, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025, PMID: 24789864) and segregated with disease in 59 affected relatives from 7 families (PMID: 20037586, PMID: 26948711, PMID: 30230566, PMID: 20037588, PMID: 20037587, PMID: 20460441, PMID: 24575025). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in at least two unrelated individuals with confirmed maternity and paternity (PMID: 24789864, PMID: 30230566). This variant has also been reported in ClinVar (Variation ID: 5000) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg269His variant may impact protein function (PMID: 21454511, PMID: 21288981, PMID: 20037588, PMID: 20037586). However, these types of assays may not accurately represent biological function. 2 additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg269Ser and p.Arg269Cys, have been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 20037586, 21336783, 24789864, 25900305, 26110311; Variation ID: 536867, 5002). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein.In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant TRPV4-related disease. ACMG/AMP Criteria applied: PS2_Moderate, PS3, PS4, PM2_Supporting, PM5_Supporting, PP1_strong (Richards 2015). - |
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 | Jun 20, 2016 | - - |
Spondylometaphyseal dysplasia, Kozlowski type;C0265281:Metatropic dysplasia;C0432227:Brachyrachia (short spine dysplasia);C0751335:Scapuloperoneal spinal muscular atrophy;C1838492:Neuronopathy, distal hereditary motor, autosomal dominant 8;C1847406:Familial digital arthropathy-brachydactyly;C1853710:Charcot-Marie-Tooth disease axonal type 2C;C1868616:Parastremmatic dwarfism;C3150755:Sodium serum level quantitative trait locus 1;C3159322:Spondyloepimetaphyseal dysplasia, Maroteaux type;C4479260:Avascular necrosis of femoral head, primary, 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Neuromuscular disease Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
D;D;D;B
Vest4
MutPred
Gain of catalytic residue at F273 (P = 0.012);Gain of catalytic residue at F273 (P = 0.012);Gain of catalytic residue at F273 (P = 0.012);.;
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