ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.918G>A (p.Trp306Ter) (rs121913007)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181248 SCV000233527 pathogenic not provided 2011-10-05 criteria provided, single submitter clinical testing This variant is denoted Trp306Stop (aka W306X) at the protein level and c.918 G>A at the cDNA level. A G>A nucleotide substitution was identified in exon 8 of the DSG2 gene, resulting in the replacement of the normal Tryptophan codon (TGG) with a Stop codon (TGA) at amino acid position 306 in the desmoglein-2 gene, was identified. Autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not always meet established clinical criteria. ARVC may be caused by mutations in at least seven genes, which together account for ARVC in 40-50% of patients (6). At least 12% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSG2 gene ( McNally E et al., Gene Review; OMM). The Trp306Stop mutation and the Arg49His mutation (also reported as Arg48His/Trp305Stop due to a difference in nomenclature) have been seen together in at least one patient (Awad, M et al., 2006) and are reported together in other publications, but it is unclear if data stem from unrelated probands with ARVC (Den Haan, A et al., 2009; Tan B et al., 2010). In the Awad 2006 (Awad, M et al., 2006) report, the proband's unaffected mother and sister also harbored the Trp306Stop mutation, but not the Arg49His mutation (Awad, M et al., 2006). Trp306Stop is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The Arg49His mutation has been reported in up to four other patients with ARVC, and has not been detected in at least 400 population-matched control chromosomes (Den Haan, A et al., 2009; Xu T et al., 2010; Barahona-Dussault, C et al., 2010). The Arg49 residue is reported to be absolutely conserved in all species and sub-types of desmoglein, and replacement with other residues is predicted to abolish a cleavage site in demoglein, disrupting production of mature, functional protein (Awad, M et al., 2006). Also, Arg49His has been seen in other unrelated individuals at GeneDx. The variant is found in ARVC panel(s).
OMIM RCV000018304 SCV000038583 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2006-07-01 no assertion criteria provided literature only

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