Submissions for variant NM_001943.5(DSG2):c.523+1G>A

dbSNP: rs553299589

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695986	SCV000824527	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-07-19	criteria provided, single submitter	clinical testing	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).
Color Diagnostics, LLC DBA Color Health	RCV001179059	SCV001343641	uncertain significance	Cardiomyopathy	2023-07-11	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001582662	SCV001820387	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	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)
AiLife Diagnostics, AiLife Diagnostics	RCV001582662	SCV002502701	likely pathogenic	not provided	2021-08-11	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV002281563	SCV002569966	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2022-09-08	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002345561	SCV002646054	likely pathogenic	Cardiovascular phenotype	2024-01-30	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV003995630	SCV004827538	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003995630	SCV004847971	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2016-02-29	criteria provided, single submitter	clinical testing	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.