Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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). |
Labcorp Genetics |
RCV001367081 | SCV001563416 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2021-08-31 | 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 missense change 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, which suggests that this missense change does not adversely affect protein function. 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. |
Ambry Genetics | RCV003298230 | SCV003997606 | uncertain significance | Cardiovascular phenotype | 2023-06-06 | criteria provided, single submitter | clinical testing | The p.N33S variant (also known as c.98A>G), located in coding exon 3 of the DSG2 gene, results from an A to G substitution at nucleotide position 98. The asparagine at codon 33 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV003532015 | SCV004363152 | uncertain significance | Cardiomyopathy | 2023-11-08 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 33 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/280842 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. |
All of Us Research Program, |
RCV003996610 | SCV004819405 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2024-02-05 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 33 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/280842 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. |