ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3059_3062del (p.Glu1020fs) (rs397516706)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208503 SCV000263862 pathogenic Primary dilated cardiomyopathy 2015-04-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242452 SCV000320489 likely pathogenic Cardiovascular phenotype 2019-10-09 criteria provided, single submitter clinical testing The c.3059_3062delAGAG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of 4 nucleotides between nucleotide positions 3059 and 3062, causing a translational frameshift with a predicted alternate stop codon (p.E1020Afs*18). This variant has been described in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Christensen AH et al. J Med Genet. 2010;47(11):736-44; Rasmussen TB et al. Hum Mutat. 2013;34(5):697-705). In another study, this variant was observed to co-segregate with ARVC in three siblings; however, two additional first-degree relatives with this variant in the same family exhibited either absent or limited clinical phenotype suggesting reduced penetrance (Lahtinen AM et al. Heart Rhythm. 2011;8(8):1214-21). The functional mechanism of DSG2 truncating alterations leading to ARVC is not well understood; however, frameshifts are typically deleterious in nature (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405-24). As such, the c.3059_3062delAGAG variant is classified as likely pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496000 SCV000584087 likely pathogenic Dilated cardiomyopathy 1BB 2015-10-08 criteria provided, single submitter research
Invitae RCV000560883 SCV000641980 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-09-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSG2 gene (p.Glu1020Alafs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acids of the DSG2 protein. This variant is present in population databases (rs746854378, ExAC 0.007%). This variant has been reported in individuals and a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21397041, 20864495, 23381804). ClinVar contains an entry for this variant (Variation ID: 199827). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852476 SCV000995170 likely pathogenic Cardiomyopathy 2018-11-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000852476 SCV001343088 uncertain significance Cardiomyopathy 2020-10-22 criteria provided, single submitter clinical testing This variant deletes 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 23381804) and in an individual with a conduction defect (PMID: 21397041). In one family study (PMID: 21397041), this variant has been reported in a proband affected with arrhythmogenic right ventricular cardiomyopathy and his two siblings with inconclusive diagnosis (age 68 and 77). This variant was also observed in the proband's unaffected sibling (age 71) and unaffected daughter (age 28). Four unaffected relatives (age 16 - 61) did not carry this variant. This variant has been identified in 9/249404 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258113 SCV001434980 likely pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10 2019-10-31 criteria provided, single submitter clinical testing The c.3059_3062delAGAG (p.Glu1020Alafs*18) variant in the DSG2 gene is predicted to introduce a premature translational termination codon, expecting to disrupt the last 99 amino acids of the DSG2 protein. This variant has been reported in individuals and a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 21397041, 23381804). This variant is present in population databases at low frequency (gnomAD 0.003609%). Therefore, this c.3059_3062delAGAG (p.Glu1020Alafs*18) variant in the DSG2 gene is classified as likely pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000560883 SCV001190277 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-07-25 no assertion criteria provided clinical testing

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