Submissions for variant NM_001943.5(DSG2):c.437G>T (p.Arg146Leu)

gnomAD frequency: 0.00054  dbSNP: rs113451409

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172528	SCV000051379	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172528	SCV000233483	likely benign	not provided	2024-03-19	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Blueprint Genetics	RCV000208207	SCV000263849	uncertain significance	Cardiac arrest	2015-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080090	SCV000287243	likely benign	Arrhythmogenic right ventricular dysplasia 10	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243170	SCV000317781	likely benign	Cardiovascular phenotype	2020-03-10	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.
Illumina Laboratory Services, Illumina	RCV001080090	SCV000408207	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172528	SCV000883747	uncertain significance	not provided	2023-09-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770546	SCV000901993	likely benign	Cardiomyopathy	2023-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770546	SCV000903197	likely benign	Cardiomyopathy	2019-10-28	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852471	SCV000995165	uncertain significance	Hypertrophic cardiomyopathy	2018-10-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172528	SCV001151510	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037305	SCV005205298	likely benign	not specified	2024-06-05	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.437G>T (p.Arg146Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (Cadherin-like) of 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 0.00039 in 249344 control chromosomes, predominantly at a frequency of 0.00076 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025). c.437G>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Mellor_2017, Nagyova_2023, Fressart_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported in one individual with Arrhythmogenic Right Ventricular Cardiomyopathy (PKP2 c.235C>T, p.Arg79X) (Nagyova_2023), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 20400443, 28600387, 37418234). ClinVar contains an entry for this variant (Variation ID: 44317). Based on the evidence outlined above, the variant was classified as likely benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001080090	SCV005398127	likely benign	Arrhythmogenic right ventricular dysplasia 10	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and dilated cardiomyopathy 1BB (MIM#612877). (SB) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD v2 (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cadherin domain (NCBI, Uniprot). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Arg146His) has been reported as likely benign (LOVD) and VUS (LOVD, ClinVar) in a clinical setting. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as likely benign and VUS (LOVD, ClinVar, PMID: 23861362). In addition, it has been described as a VUS in an individual with ARVC who also harboured a pathogenic variant in PKP2 (PMID: 20400443) and in an individual with idiopathic sudden cardiac arrest (PMID: 28600387). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037305	SCV000060962	uncertain significance	not specified	2009-09-21	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000037305	SCV000280085	uncertain significance	not specified	2013-04-25	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. Based on the information reviewed below, we classify it as a variant of unknown significance. This variant has previously been reported in one proband with ARVC who also carried a premature stop codon in PKP2, and the DSG2 variant was categorized as a variant of unknown significance (Fressart et al. 2010). There is no published segregation data. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Leucine. The Arginine at this location is highly conserved across mammalian species, but it is a Proline in birds and the amino acid varies across fish species. This variant is in the cadherin domain. Variation at nearby residues has been associated with ARVC, which may support the functional importance of this region of the protein: Val149Phe, Asp154Glu (HGMD professional version as of January 17, 2014). Kapplinger et al. have proposed a “hot spot” for DSG2 variants between amino acids 24-388 in patients with ARVC but not in controls. This variant does fall within that hot spot. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.983. In total the variant has been seen in 9 out of over 60,000 published controls and individuals from publicly available population datasets. This variant is present in 9 Caucasian individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals. Furthermore, a Arg146Cys variant at the same amino acid is present in one African-American individual. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs113451409, submitted by 6 different sequencing projects or labs. It is not present in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 1/26/2015. The variant was not observed in published controls: 300 Caucasian controls (Fressart et al. 2010). There are 37 individuals in ExAc with this variant and, of these, 1 of them is Latino, 2 are African, 1 is “other”, and 33 are Caucasian.
GenomeConnect, ClinGen	RCV000172528	SCV000606918	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172528	SCV001742076	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172528	SCV001917473	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172528	SCV001927121	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172528	SCV001959399	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172528	SCV001967197	likely benign	not provided		no assertion criteria provided	clinical testing