Submissions for variant NM_001943.5(DSG2):c.875G>A (p.Arg292His)

dbSNP: rs185821167

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037318	SCV000060975	uncertain significance	not specified	2018-01-17	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000205277	SCV000261997	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 292 of the DSG2 protein (p.Arg292His). This variant is present in population databases (rs185821167, gnomAD 0.03%). 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: 44330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000767197	SCV000622048	uncertain significance	not provided	2021-06-18	criteria provided, single submitter	clinical testing	Reported in several patients with ARVC who also harbor a second potentially disease-causing variant in the DSG2 gene (Segura-Rodriguez et al., 2020); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 44330; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25172079, 31702781, 27535533, 21606396, 26383259)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770549	SCV000901996	uncertain significance	Cardiomyopathy	2022-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770549	SCV001735670	uncertain significance	Cardiomyopathy	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 292 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 the homozygous state in several individuals affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia and in the heterozygous state in their unaffected relatives (PMID: 25172079, 31702781). This variant has also been identified in 24/280756 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.
Fulgent Genetics, Fulgent Genetics	RCV002490507	SCV002779796	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-10-09	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002490507	SCV003925213	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2022-03-15	criteria provided, single submitter	clinical testing	The c.875G>A variant identified in DSG2 has previously been reported in the literature in individuals with ARVC/D either in trans with another variant [PMID: 25172079] or heterozygous [PMID: 31702781], and it has been deposited in ClinVar as variant of uncertain significance by multiple submitters [ClinVar ID:44330]. The c.875G>A variant is observed in 58 alleles (~0.01% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases which may also include individuals with cardiac phenotypes. The c.875G>A variant is located in exon 8 of this 15-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 292 within the extracellular domain of the encoded protein. In silico predictions are inconclusive of the variant's effect [(CADD v1.6 = 25, REVEL = 0.313)]; however, thereare no functional studies to support or refute these predictions. Another variant affecting the same codon (c.874C>T:p.(Arg292Cys)) has also been reported in the literature [PMID: 28349240] and ClinVar [ClinVar ID: 466351] as variant of uncertain significance. Based on available evidence this c.875G>Ap.(Arg292His) variant identified in DSG2 is classified as a Variant of Uncertain Significance.