18-31521244-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2
The NM_001943.5(DSG2):c.523+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000131 in 1,451,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001943.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.523+1G>A | splice_donor_variant, intron_variant | ENST00000261590.13 | NP_001934.2 | |||
DSG2 | XM_047437315.1 | c.-12+1G>A | splice_donor_variant, intron_variant | XP_047293271.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.523+1G>A | splice_donor_variant, intron_variant | 1 | NM_001943.5 | ENSP00000261590.8 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 150806Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000420 AC: 1AN: 238030Hom.: 0 AF XY: 0.00000774 AC XY: 1AN XY: 129154
GnomAD4 exome AF: 0.0000131 AC: 19AN: 1451740Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9AN XY: 721696
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 150806Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73524
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 188446). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 27532257, 33238575; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 5 of the DSG2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 27, 2024 | Criteria applied: PVS1,PS4_MOD - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 11, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2023 | Reported in individuals with cardiomyopathy (primarily ARVC) and coronary artery disease (CAD)-related sudden cardiac death (SCD) (Walsh et al., 2017; Daoud et al., 2019; Hermida et al., 2019; Vahatalo et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30790397, 28471438, 35087879, 27532257, 31402444, 30731207, 35747619, 36556183, 28600387, 35653365, 37183561) - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 29, 2016 | The c.523+1G>A variant in DSG2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splicing and other truncating variants in the DSG2 gene are established as disease-causing for ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.523+1G>A variant is likely pathogenic for ARVC. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant causes a G>A nucleotide substitution at the +1 position of intron 5 of the DSG2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with arrhythmogenic right ventricular cardiomyopathy including one who was homozygous (PMID: 27532257, 28600387, 30790397, ClinVar SCV002569966.1), and in another individual affected with sudden cardiac death with single vessel coronary artery disease and hypertrophied heart (PMID: 35087879). This variant has been identified in 1/238030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Sep 08, 2022 | We observed a с.523+1G>A genetic variant in the DSG2 gene in a 20-y.o. proband and her 51-y.o. father, both diagnosed with arrhythmogenic right ventricular cardiomyopathy. This variant is not present in LOVD database, not observed at significant frequency in large population cohorts (gnomAD v3.1.2). Online bioinformatic resources classify the с.523+1G>A variant as probably pathogenic. It is expected to result in splice sites changes in mRNA. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30790397, 28471438, 35087879, 27532257). Due to the fact that our patients were also diagnosed with ARVC, we assume that the с.523+1G>A variant could be classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | The c.523+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the DSG2 gene. This alteration has been reported in cardiomyopathy cohorts, including arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts, as well as a sudden cardiac arrest cohort (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 02;19:192-203; Daoud H et al. J Mol Diagn, 2019 05;21:437-448; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Ye JZ et al. Clin Genet, 2019 12;96:506-514). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 11, 2023 | This variant causes a G>A nucleotide substitution at the +1 position of intron 5 of the DSG2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with arrhythmogenic right ventricular cardiomyopathy including one who was homozygous (PMID: 27532257, 28600387, 30790397, ClinVar SCV002569966.1), and in another individual affected with sudden cardiac death with single vessel coronary artery disease and hypertrophied heart (PMID: 35087879). This variant has been identified in 1/238030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at