Submissions for variant NM_001943.4(DSG2):c.1015del

dbSNP: rs794728094

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181241	SCV000233520	likely pathogenic	not provided	2016-07-12	criteria provided, single submitter	clinical testing	Although the c.1015delG likely pathogenic variant in the DSG2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Glutamic acid 339, changing it to a Lysine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Glu339LysfsX2. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the DSG2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). Furthermore, the c.1015delG variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852263	SCV002242443	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu339Lysfs*2) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 199825). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000181241	SCV002502795	likely pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002463439	SCV002633957	pathogenic	Cardiovascular phenotype	2020-08-19	criteria provided, single submitter	clinical testing	The c.1015delG mutation, located in coding exon 9 of the DSG2 gene, results from a deletion of one nucleotide at nucleotide position 1015, causing a translational frameshift with a predicted alternate stop codon (p.E339Kfs*2). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001808460	SCV002051910	uncertain significance	Cardiomyopathy	2021-02-22	flagged submission	clinical testing	This variant deletes one nucleotide in exon 9 of the DSG2 gene, creating a frameshift and premature translation stop signal. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional RNA assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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 DSG2 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.