Submissions for variant NM_001943.5(DSG2):c.1376A>G (p.Tyr459Cys)

gnomAD frequency: 0.00003  dbSNP: rs576404380

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000755675	SCV000221465	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-06-08	criteria provided, single submitter	research	Downgraded variant due to updated local frequency
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171268	SCV000697882	likely benign	not provided	2016-02-01	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.1376A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict a damaging outcome for this variant, however, functional studies have not been carried out to confirm these predictions. This variant is found in 139/111860 control chromosomes (5 homozygotes) at a frequency of 0.0012426. The variant is predominantly found in South Asians (132/15646; 0.0084367). These frequencies are 124-843 times the maximal expected frequency of a pathogenic DSG2 allele (0.00001), highly suggesting this variant is benign. Additionally, the variant has been reported in 1 HCM patient to co-occur with a pathogenic variant, TNNT2 R92W. Although one research center reports this variant as likely pathogenic, they provide no evidence to independently evaluate. Taken together, this is probably a normal variant given the high frequency in controls and at least one reported co-occurrence with a pathogenic TNNT2 allele, thus this DSG2 variant was classified as likely benign.
GeneDx	RCV000606666	SCV000714891	benign	not specified	2017-04-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000617986	SCV000737979	benign	Cardiovascular phenotype	2017-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000776131	SCV000911079	benign	Cardiomyopathy	2018-10-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755675	SCV001003479	benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755675	SCV001284603	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776131	SCV001334033	benign	Cardiomyopathy	2018-03-12	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000606666	SCV001925083	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000171268	SCV001928691	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171268	SCV001972067	likely benign	not provided		no assertion criteria provided	clinical testing