Submissions for variant NM_024422.6(DSC2):c.304G>A (p.Glu102Lys)

gnomAD frequency: 0.00070  dbSNP: rs144799937

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039432	SCV000063116	likely benign	not specified	2023-09-21	criteria provided, single submitter	clinical testing	The p.Glu102Lys variant in DSC2 is classified as likely benign because it has been identified in 0.1% (164/128778) of European chromosomes and 0.2% (22/10356) of Ashkenazi Jewish chromosomes by gnomAD (http://exac.broadinstitute.org), which is higher than the maximal expected allele frequency for a pathogenic variant in DSC2. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a lysine (Lys) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also suggest that the p.Glu102Lys variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4.
CSER _CC_NCGL, University of Washington	RCV000148467	SCV000190167	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in 2 unrelated patients having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Blueprint Genetics	RCV000039432	SCV000206894	likely benign	not specified	2015-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001172124	SCV000233412	likely benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21606390, 23299917, 25637381, 25569433, 17963498, 26310507, 20197793, 23147450, 23396983, 27301361, 28798025, 29802319, 31568572, 31402444)
Invitae	RCV000232838	SCV000290736	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000248994	SCV000320061	likely benign	Cardiovascular phenotype	2018-09-19	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000232838	SCV000743499	likely benign	Arrhythmogenic right ventricular dysplasia 11	2017-07-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769503	SCV000900898	likely benign	Cardiomyopathy	2022-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769503	SCV000902951	likely benign	Cardiomyopathy	2018-08-06	criteria provided, single submitter	clinical testing	Likely Benign based on current evidence: This missense variant is located in the N-terminal propeptide sequence of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that this variant may cause the protein to localize to the cytoplasm in addition to the cell-cell junction (PMID: 17963498). However, biological significance of this finding is unknown. This variant has been reported in individuals with arrhythmogenic, dilated and hypertrophic cardiomyopathy (PMID: 17963498, 20197793, 21606390, 23147450, 23396983) but has also been detected in unaffected family members (PMID: 17963498, 23147450). This variant is common in the general population and has been identified in 156/126324 non-Finnish European chromosomes (0.12%) and 21/10134 Ashkenazi Jewish chromosomes (0.21%) by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on collective evidence, this variant is classified as Likely Benign.
Illumina Laboratory Services, Illumina	RCV000232838	SCV001285908	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001172124	SCV001335076	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	DSC2: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039432	SCV001361043	likely benign	not specified	2019-10-08	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the Cadherin prodomain (IPR014868) of the enoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251372 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European and 0.0022in the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European and Ashkenazi Jewish control individuals in the gnomAD database is approximately 8- and 13- fold higher (respectively) than the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD) phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.304G>A, has been reported in the literature in individuals affected with ARVD (Beffagna_2007, Quarta_2011, Anastasakis_2012), it has also been detected in unaffected family members (Beffagna_2007, Anastasakis_2012). The variant has also been detected in individuals affected with other cardiomyopathies (hypertrophic cardiomyopathy; Lopes_2012 and left-ventricular non-compaction; Miszalski-Jamka_2017), as well as healthy control populations (Andereasen_2013, Amendola_2015, Hall_2018). One publication reported experimental evidence evaluating an impact on protein function, and indicated that the variant may disrupt localization of the protein to the plasma membrane, however, this study does not allow convincing conclusions about the variant effect (Beffagna_2007). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (6 laboratories cited the variant as likely benign, while 3 cited the variant as VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000039432	SCV000280078	uncertain significance	not specified	2014-12-07	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the variant has been observed in disparate phenotypes and is present with an MAF >0.1% in samples unselected for ARVC, we consider this variant a variant of uncertain significance. The variant has been reported in the literature in at least 5 individuals with ARVC (Beffagna 2007, De Bertoli et al 2010, Quarta 2011, Anastasakis 2012). Per the LMM ClinVar submission: "In vitro functional studies suggest that the p.Glu102Lys variant may disrupt proper localization of the protein (Beffagna 2007). However, these types of assays may not accurately represent biological function. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a Lysine (Lys) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also suggest that the p.Glu102Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity." The variant was reported online in 89 of 60,526 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). Specifically, the highest frequency was in Europeans with 71/33283 (MAF 0.11%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000232838	SCV000733781	likely benign	Arrhythmogenic right ventricular dysplasia 11		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001172124	SCV001951195	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001172124	SCV001970776	likely benign	not provided		no assertion criteria provided	clinical testing