Submissions for variant NM_001943.5(DSG2):c.1781T>C (p.Leu594Pro)

gnomAD frequency: 0.00038  dbSNP: rs199681901

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172530	SCV000050911	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037272	SCV000060929	uncertain significance	not specified	2014-08-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Leu594Pro varia nt in DSG2 has been identified in 4/8470 European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs19968190 1). Our laboratory has previously detected this variant in 3 individuals (1 Asia n child with HCM and WPW, 1 Ashkenazi Jewish adult with possible DCM/ARVC, and 1 Ashkenazi Jewish adult with HCM). Leucine (Leu) at position 594 is not conserve d in mammals or evolutionarily distant species, raising the possibility that a c hange at this position may be tolerated. Additional computational prediction too ls suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clini cal significance of the Leu594Pro variant is uncertain, these data suggest that it is more likely to be benign.
Invitae	RCV001085411	SCV000561400	likely benign	Arrhythmogenic right ventricular dysplasia 10	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000037272	SCV000714372	likely benign	not specified	2018-01-22	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	RCV000618191	SCV000735732	likely benign	Cardiovascular phenotype	2018-03-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000776195	SCV000911324	benign	Cardiomyopathy	2018-08-14	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852742	SCV000995459	likely benign	Primary dilated cardiomyopathy	2018-04-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001085411	SCV001286958	benign	Arrhythmogenic right ventricular dysplasia 10	2018-05-11	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172530	SCV002822452	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	DSG2: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776195	SCV003838788	likely benign	Cardiomyopathy	2021-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037272	SCV004241802	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.1781T>C (p.Leu594Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 249162 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), suggesting that the variant is benign. c.1781T>C has been reported in the literature in a heterozygous individual affected with Brugada syndrome (e.g. DiResta_2015) and in a case of sudden infant death syndrome reported as a VUS (e.g. Neubauer_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26220970, 21636032, 28074886). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=3), likely benign (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003952429	SCV004768410	likely benign	DSG2-related condition	2024-02-13	criteria provided, single submitter	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).
Clinical Genetics, Academic Medical Center	RCV000037272	SCV001924538	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172530	SCV001975715	likely benign	not provided		no assertion criteria provided	clinical testing