Submissions for variant NM_001943.5(DSG2):c.1880-2A>G

dbSNP: rs397514038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211716	SCV000060933	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2010-12-17	criteria provided, single submitter	clinical testing	The 1880-2A>G variant has been reported in two siblings with ARVC and was absent from 560 matched control chromosomes, supporting a pathogenic role. However, b oth siblings also carried a second, possibly disease causing variant on the othe r copy of the DSG2 gene (Pilichou, 2006). RNA studies demonstrated that the 1880 -2A>G abolishes the splice site, leading to the use of a cryptic splice site 38 bp downstream. The aberrantly spliced mRNA was shown to lack the first 38 bp of exon 13, which is predicted to cause a frameshift starting at position 627 and p remature termination 19 amino acids later, leading to a truncated or absent prot ein (Pilichou, 2006). In summary, the severity of the change as well as absence from controls suggest that this variant is likely pathogenic.
GeneDx	RCV000181225	SCV000233504	pathogenic	not provided	2020-03-17	criteria provided, single submitter	clinical testing	Identified in association with ARVC (Pilichou et al., 2006; Walsh et al., 2017); variant reported as c.1881-2 A>G (due to alternate nomenclature) in an affected patient and her sister who both also harbored a missense variant in the DSG2 gene (Pilichou et al 2006); Published functional studies demonstrate that this variant leads to the inactivation of the natural intron 12 splice acceptor site and the activation of a cryptic splice acceptor site in exon 13, resulting in abnormal gene splicing (Pilichou et al., 2006); Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as either pathogenic or likely pathogenic (ClinVar Variant ID# 16817; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16505173, 23381804, 25525159, 27532257, 31402444, 32686758)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000018310	SCV000814564	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-04-10	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the DSG2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 27532257). This variant is also known as c.1881-2A>G. ClinVar contains an entry for this variant (Variation ID: 16817). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 16505173). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000181225	SCV005041065	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	DSG2: PVS1, PM2, PS4:Moderate
All of Us Research Program, National Institutes of Health	RCV000211716	SCV005428718	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-07-29	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -2 position of intron 12 of the DSG2 protein. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 38 nucleotides downstream of the native intron 12 splice site. A functional RNA study has shown that this cryptic splice acceptor site is used, leading to a deletion of 38 nucleotides (PMID: 16505173). As a result, this variant is expected to create a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 24704780, 26138720, 27532257). Some of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: PMID: 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic 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.
OMIM	RCV000018310	SCV000038589	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2006-03-07	no assertion criteria provided	literature only