18-31524748-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM5PP3_ModerateBS2
The NM_001943.5(DSG2):c.874C>T(p.Arg292Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,930 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.874C>T | p.Arg292Cys | missense_variant | 8/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.340C>T | p.Arg114Cys | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.874C>T | p.Arg292Cys | missense_variant | 8/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000682087.2 | n.705C>T | non_coding_transcript_exon_variant | 6/6 | |||||
DSG2 | ENST00000683614.2 | n.705C>T | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249360Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135300
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461852Hom.: 0 Cov.: 35 AF XY: 0.0000646 AC XY: 47AN XY: 727224
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74264
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 13, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2021 | 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: 30454721, 21606396, 28097316, 25820315, 22000064, 22214898, 27532257, 29178656) - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | Cardiac Research Department, West China Second University Hospital | Jan 01, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 05, 2024 | This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757). One of the affected individuals also carried a pathogenic PKP2 truncation variant, which could explain the disease observed in that individual (PMID: 22214898). This variant has also been identified in 12/249360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 292 of the DSG2 protein (p.Arg292Cys). This variant is present in population databases (rs770921270, gnomAD 0.02%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721). ClinVar contains an entry for this variant (Variation ID: 466351). 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 not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 13, 2020 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_Mod,PM2,PP3,PP4. This variant was detected in homozygous state. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 20, 2023 | This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757, 36138163). Two of the affected individuals also carried a pathogenic PKP2 variant, which could explain the disease observed in that individual (PMID: 22214898, 36138163). This variant has also been identified in 12/249360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2020 | The p.R292C variant (also known as c.874C>T), located in coding exon 8 of the DSG2 gene, results from a C to T substitution at nucleotide position 874. The arginine at codon 292 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Te Riele ASJM et al. JACC Clin Electrophysiol, 2015 Dec;1:551-560; Walsh R et al. Genet. Med., 2017 02;19:192-203). However, in many probands this alteration was detected in the homozygous or compound heterozygous state or co-occurred with alterations in other ARVC-associated genes, and a number of relatives positive for the R292C alteration were reported to be unaffected (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Sato T et al. Leg Med (Tokyo), 2011 Nov;13:298-300; Nakajima T et al. Circ. J., 2012 Dec;76:737-43; Wada Y et al. Mol Genet Genomic Med, 2017 11;5:639-651). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at