ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.98A>G (p.Asn33Ser) (rs727505205)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181196 SCV000233474 uncertain significance not provided 2012-11-21 criteria provided, single submitter clinical testing p.Asn33Ser (AAT>AGT): c.98 A>G in exon 3 of the DSG2 gene (NM_001943.3). The Asn33Ser variant in the DSG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn33Ser results in a conservative amino acid substitution of one neutral, polar residue with another at a position that is not conserved across species. Therefore, in silico algorithms predict Asn33Ser does not alter the protein's structure/function. No pathogenic mutations have been reported in near proximity of Asn33Ser, indicating this region of the protein may be tolerant of change (Van der Zwaag P et al., 2009). Although these findings indicate that Asn33Ser is likely a benign variant, it was not reported in the 1000 Genomes database (Kersey P et al., 2010), and the NHLBI ESP Exome Variant Project has not identified Asn33Ser in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. With the information available at this time, we cannot definitively determine if Asn33Ser is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV001367081 SCV001563416 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-01-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 33 of the DSG2 protein (p.Asn33Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs727505205, ExAC 0.003%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 199795). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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