Submissions for variant NM_024422.6(DSC2):c.1123C>T (p.Arg375Ter)

gnomAD frequency: 0.00001  dbSNP: rs794728075

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755674	SCV000883078	uncertain significance	Pigmented nodular adrenocortical disease, primary, 2	2018-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001585688	SCV001818572	likely pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing	Reported as an ACMG secondary finding in individuals who underwent whole exome sequencing; detailed clinical information was not provided (Sapp et al., 2018; Thauvin-Robinet et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32686758, 31402444, 31019283, 30122538, 23911551)
Invitae	RCV001855862	SCV002129649	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2021-10-23	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This sequence change creates a premature translational stop signal (p.Arg375*) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is present in population databases (no rsID available, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 617896). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001585688	SCV002822450	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	DSC2: PVS1
Baylor Genetics	RCV001855862	SCV004040851	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2023-04-03	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001855862	SCV004239085	pathogenic	Arrhythmogenic right ventricular dysplasia 11	2023-08-21	criteria provided, single submitter	clinical testing	This DSC2 variant (rs794728075) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 2/251006 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar and in the literature as a secondary finding following genomic-based testing. This nonsense variant results in a premature termination codon (PTC) in exon 9 of 16, likely leading to nonsense-mediated decay and lack of protein production. Bioinformatic analysis predicts that this missense variant would not affect normal exon 9 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1123C>T (p.Arg375Ter) to be pathogenic for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).