Submissions for variant NM_001943.5(DSG2):c.2368C>T (p.His790Tyr)

gnomAD frequency: 0.00130  dbSNP: rs114544564

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154627	SCV000204301	likely benign	not specified	2014-05-28	criteria provided, single submitter	clinical testing	His790Tyr in exon 15 of DSG2: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (15/3672) of African American ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs114544564).
GeneDx	RCV000845294	SCV000512869	likely benign	not provided	2021-01-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20031617)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086616	SCV000561393	likely benign	Arrhythmogenic right ventricular dysplasia 10	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618561	SCV000734908	likely benign	Cardiovascular phenotype	2018-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000771841	SCV000904555	likely benign	Cardiomyopathy	2018-10-29	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845294	SCV000987325	likely benign	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086616	SCV001283591	likely benign	Arrhythmogenic right ventricular dysplasia 10	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154627	SCV001437287	likely benign	not specified	2020-09-08	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.2368C>T (p.His790Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 283014 control chromosomes, predominantly at a frequency of 0.0038 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 380 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2368C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV002478453	SCV002802302	likely benign	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-08-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002478453	SCV003919890	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-03-30	criteria provided, single submitter	clinical testing	DSG2 NM_001943.4 exon 15 p.His790Tyr (c.2368C>T): This variant has not been reported in the literature and is present in 0.3% (93/24196) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-29125717-C-T). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:177961). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771841	SCV004240503	benign	Cardiomyopathy	2023-01-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998257	SCV004821788	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000845294	SCV005215251	likely benign	not provided		criteria provided, single submitter	not provided
CeGaT Center for Human Genetics Tuebingen	RCV000845294	SCV005331314	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	DSG2: BP4
PreventionGenetics, part of Exact Sciences	RCV003927491	SCV004743835	likely benign	DSG2-related disorder	2020-01-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).