Submissions for variant NM_001943.5(DSG2):c.1652-12C>T

gnomAD frequency: 0.00173  dbSNP: rs140850369

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037269	SCV000060926	likely benign	not specified	2012-04-25	criteria provided, single submitter	clinical testing	1652-12C>T in Intron 11 of DSG2: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (13/3106) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs140850369). 1652-12C>T in intron 11 of DS G2 (rs140850369, allele frequency = 0.4%, 13/3106)
GeneDx	RCV000037269	SCV000168240	benign	not specified	2014-05-29	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.
Illumina Laboratory Services, Illumina	RCV001127624	SCV001286957	benign	Arrhythmogenic right ventricular dysplasia 10	2017-05-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001186905	SCV001353515	benign	Cardiomyopathy	2018-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037269	SCV001623424	benign	not specified	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.1652-12C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0004 in 248862 control chromosomes, predominantly at a frequency of 0.0052 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), 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.1652-12C>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001127624	SCV002361127	benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-29	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001529425	SCV005215246	likely benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529425	SCV001742864	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037269	SCV001922754	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529425	SCV001928058	likely benign	not provided		no assertion criteria provided	clinical testing