rs267607143
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_021625.5(TRPV4):c.943C>T(p.Arg315Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R315Q) 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 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.943C>T | p.Arg315Trp | missense_variant | 6/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.943C>T | p.Arg315Trp | missense_variant | 6/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727216
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 24, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 315 of the TRPV4 protein (p.Arg315Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor and sensory neuropathy type 2C (HMSN2C), scapuloperoneal spinal muscular atrophy (SPSMA), Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis, and congenital distal SMA (PMID: 20037588, 20460441, 21115951, 22065612). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4999). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TRPV4 function (PMID: 20037588, 21454511, 22702953). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2022 | Not observed 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: 21115951, 21454511, 22702953, 20037588, 31191204, 31041394, 24830047, 32579787, 34426522, 33664271, 32481620) - |
Scapuloperoneal spinal muscular atrophy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | research | Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University | Mar 31, 2020 | - - |
TRPV4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2024 | The TRPV4 c.943C>T variant is predicted to result in the amino acid substitution p.Arg315Trp. This variant has been reported in multiple individuals with TRPV4-related autosomal dominant conditions, including scapuloperoneal spinal muscular atrophy, and functional studies support its pathogenicity (Auer-Grumbach et al. 2010. PubMed ID: 20037588; Fecto et al. 2011. PubMed ID: 21454511; Inada et al. 2012. PubMed ID: 22702953). It has been reported as a de novo finding, and also to segregate with affected status in families (Faye et al. 2019. PubMed ID: 31191204; Chen et al. 2010. PubMed ID: 21115951; ClinVar Variation ID: 4999). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2022 | The c.943C>T (p.R315W) alteration is located in exon 6 (coding exon 5) of the TRPV4 gene. This alteration results from a C to T substitution at nucleotide position 943, causing the arginine (R) at amino acid position 315 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected as de novo in an individual with Kozslowski type spondylometaphyseal dysplasia and Charcot-Marie-Tooth disease type 2C (CMT2C) (Faye, 2019). It has also been found to segregate with TRPV4-related disorders such as congenital distal spinal muscular atrophy (CDSMA), scapuloperoneal spinal muscular atrophy (SPSMA), and hereditary motor and sensory neuropathy type IIc (HMSN2C) in multiple families (Chen, 2010; Auer-Grumbach, 2010). This alteration has been described in additional unrelated individuals with TRPV4-related disorders (Tunca, 2020; Velilla, 2019; Aharoni, 2011; Echaniz-Laguna, 2014). Based on the available evidence, this alteration is classified as pathogenic. - |
Neuronopathy, distal hereditary motor, autosomal dominant 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
TRPV4-Associated Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a heterozygous change in families with hereditary motor and sensory neuropathy type 2C, scapuloperoneal spinal muscular atrophy, Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis and congenital distal SMA (PMID: 20037588, 21115951, 20460441, 22065612). Functional studies show that this variant alters the localization of the TRPV4 protein to the cell surface and increases the basal calcium levels leading to increased cell death (PMID: 20037588, 22702953, 21454511). The c.943C>T (p.Arg315Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.943C>T (p.Arg315Trp) variant is classified as Pathogenic. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at