Submissions for variant NM_001943.5(DSG2):c.829_840del (p.Leu277_Met280del)

dbSNP: rs794728093

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181240	SCV000233519	pathogenic	not provided	2015-04-03	criteria provided, single submitter	clinical testing	The c.829_840del12 mutation has been reported as a disease-causing mutation in association with ARVC (Syrris P et al., 2007, Asimaki A et al., 2009). This mutation was present in a parent and child, both of whom met Task Force criteria for the diagnosis of ARVC. Another child from this family with autopsy-confirmed ARVC also harbored this mutation (Syrris P et al., 2007). The mutation was absent from 200 ethnicity-matched control samples in this study. Furthermore, immunohistochemical analysis of cardiac tissue from autopsy in an individual with this mutation showed marked reduction in immunoreactivity for plakophilin2 and desmoplakin when compared to control tissue (Asimaki A et al., 2009). This mutation results in the deletion of 4 amino acids at the beginning of exon 8, that it is predicted to destroy the normal acceptor site of intron 7 and to create a cryptic splice acceptor site in exon 8. In addition, the NHLBI ESP Exome Variant Server reports c.829_840del12 was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, c.829_840del12 in the DSG2 gene is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642315	SCV000763984	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-31	criteria provided, single submitter	clinical testing	This variant, c.829_840del, results in the deletion of 4 amino acid(s) of the DSG2 protein (p.Leu277_Met280del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779260860, gnomAD 0.0008%). This variant has been observed in individual(s) with DSG2-related conditions (PMID: 17105751). This variant is also known as c.829-1delGCTTGAAGGGAT (G277fsX278), 829_840delCTTGAAGGCATG. ClinVar contains an entry for this variant (Variation ID: 199824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001525778	SCV001735966	uncertain significance	Cardiomyopathy	2023-05-18	criteria provided, single submitter	clinical testing	This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy and it has been observed to segregate with disease in one of the families (PMID: 17105751, 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000181240	SCV002502970	uncertain significance	not provided	2021-11-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002464009	SCV002679255	uncertain significance	Cardiovascular phenotype	2019-10-24	criteria provided, single submitter	clinical testing	The c.829_840del12 variant (also known as p.L277_M280del) is located in coding exon 8 of the DSG2 gene. This variant results from an in-frame CTTGAAGGGATG deletion at nucleotide positions 829 to 840. This results in the deletion of four amino acids between codons 277 and 280. This variant was detected in two related individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who shared an additional first degree relative with sudden cardiac death due to ARVC, but who did not have genetic testing (Syrris P et al. Eur. Heart J., 2007 Mar;28:581-8). These amino acid positions are generally not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525778	SCV003838785	likely pathogenic	Cardiomyopathy	2021-08-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996626	SCV004819477	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. Splicing prediction tools suggest that this variant may not disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in a small family (PMID: 17105751), as well as in two unrelated individuals with this condition (PMID: 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 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.