ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.829_840del (p.Leu277_Met280del) (rs794728093)

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Total submissions: 3
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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.
Invitae RCV000642315 SCV000763984 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-03-02 criteria provided, single submitter clinical testing This variant, c.829_840delCTTGAAGGGATG, 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, ExAC 0.002%). This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in a single family (PMID: 17105751). It has also been observed in several individuals with this condition and in one of these individuals, other pathogenic alleles were also identified in PKP2 (PMID: 19279339, 23671136). This variant is also known as c.829-1delGCTTGAAGGGAT (G277fsX278) or 829_840delCTTGAAGGCATG in the literature. ClinVar contains an entry for this variant (Variation ID: 199824). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 Health, Inc RCV001525778 SCV001735966 uncertain significance Cardiomyopathy 2020-12-07 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.

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