Submissions for variant NM_001943.5(DSG2):c.91del (p.Thr31fs)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480668	SCV000572223	likely pathogenic	not provided	2016-11-15	criteria provided, single submitter	clinical testing	Although the c.91delA likely pathogenic variant in the DSG2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Threonine 31, changing it to a Glutamine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Thr31GlnfsX14. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the DSG2 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.91delA variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.91delA in the DSG2 gene is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865472	SCV002241855	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr31Glnfs*14) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). This variant is present in population databases (rs758282201, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422697). For these reasons, this variant has been classified as Pathogenic.

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