rs267607146
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP2PP5_Very_StrongBP4
The NM_021625.5(TRPV4):c.805C>T(p.Arg269Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,054 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_021625.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.805C>T | p.Arg269Cys | missense_variant | 5/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.805C>T | p.Arg269Cys | missense_variant | 5/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Published Functional studies show that R269C alters the channel activity and leads to increased rate of cell death (Landour et al., 2010).; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20460441, 35170874, 31468327, 21336783, 22702953, 26110311, 24963089, 22617546, 24789864, 33664271, 31041394, 33820833, 25900305, 20037586, 22851605) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 269 of the TRPV4 protein (p.Arg269Cys). This variant is present in population databases (rs267607146, gnomAD 0.01%). This missense change has been observed in individual(s) with TRPV4-related neuropathy (PMID: 20037586, 21336783, 24789864, 25900305, 26110311). 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: 5002). 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. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037586, 22702953). 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: 20037587, 20037588, 24575025, 24963089, 26948711, 27751652). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2022 | The p.R269C pathogenic mutation (also known as c.805C>T), located in coding exon 4 of the TRPV4 gene, results from a C to T substitution at nucleotide position 805. The arginine at codon 269 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported to be de novo in individuals with skeletal dysplasia and scapuloperoneal spinal muscular atrophy (SPSMA) and distal hereditary motor neuropathy (dHMN) (Evangelista et al. Neuromuscul Disord, 2015 Jun;25:516-21; Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26). In addition, this variant was identified in multiple unrelated individuals with TRPV-related disease (Deng S et al. Neuromolecular Med, 2020 Mar;22:68-72; Echaniz-Laguna A et al. Neurology, 2014 May;82:1919-26; Berciano et al. J Neurol. 2011 Aug;258:1413-21). Functional studies indicate that this alteration impairs normal channel activity, mitochondrial transport in axons, and neuronal projections in Drosophila and increases cytotoxicity in vitro (Woolums et al. Nat Commun, 2020 May 29;11:2679; Velilla et al. Neurol Genet, 2019 Mar 7;5:e312.). Another alteration at the same codon, p.R269H (c.806 G>A), has been detected in individuals with Charcot-Marie-Tooth disease (CMT), scapuloperoneal spinal muscular atrophy (SPSMA), congenital distal spinal muscular atrophy (CDSMA) and arthrogryposis, with some functional evidence (Landoure et al. Nat Genet, 2010 Feb;42:170-4; Auer-Grumbach et al. Nat Genet, 2010 Feb;42:160-4; Deng et al. Nat Genet. 2010 Feb;42:165-9.). This amino acid position is well conserved in available vertebrate species; however, cysteine is the reference amino acid in other vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Neuronopathy, distal hereditary motor, autosomal dominant 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Hereditary motor neuron disease Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | Inherited Neuropathy Consortium | - | - - |
Scapuloperoneal spinal muscular atrophy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Distal spinal muscular atrophy Uncertain:1
Uncertain significance, no assertion criteria provided | research | Genesis Genome Database | Aug 14, 2019 | - - |
Neuromuscular disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at