Submissions for variant NM_004415.4(DSP):c.5218G>A (p.Glu1740Lys)

gnomAD frequency: 0.00091  dbSNP: rs142885240

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172543	SCV000051388	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038062	SCV000061728	likely benign	not specified	2020-04-20	criteria provided, single submitter	clinical testing	The p.Glu1740Lys variant in DSP is classified as likely benign because it has been identified in 0.2% (73/35312) of Latino and 0.18% (229/129084) of European chromosomes, including 1 homozygous individual by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in >10 individuals with a range of cardiomyopathy phenotypes (ARVC, DCM, HCM, RCM, Brugada syndrome, ventricular tachycardia), and it has segregated with Brugada syndrome in 1 affected relative from 1 family (Cox 2011, Allegue 2015, Bottillo 2016, LMM data). However, these diseases have different underlying molecular mechanisms, and furthermore, several of these probands were compound or double heterozygous with a presumed pathogenic variant. In summary, this variant is likely benign due to its elevated frequency in the general population, presence of phenotypes with different underlying molecular mechanisms in reported cases, as well as cases that had other more likely causative variants identified. ACMG/AMP Criteria applied: BS1, BP5, BP4.
GeneDx	RCV000172543	SCV000233547	likely benign	not provided	2021-03-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21606396, 31395126, 26230511, 23861362, 26656175, 27153395, 27435932, 24503780, 30821013)
Invitae	RCV001082740	SCV000288543	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000376629	SCV000465106	likely benign	Lethal acantholytic epidermolysis bullosa	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001095215	SCV000465107	likely benign	Arrhythmogenic right ventricular dysplasia 8	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000406700	SCV000465109	likely benign	Woolly hair-skin fragility syndrome	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415071	SCV000492553	uncertain significance	Primary dilated cardiomyopathy; Migraine; Hemiplegia	2014-11-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172543	SCV000702977	uncertain significance	not provided	2016-11-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621777	SCV000735617	likely benign	Cardiovascular phenotype	2018-08-01	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000038062	SCV000747953	uncertain significance	not specified	2017-01-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769232	SCV000900608	benign	Cardiomyopathy	2021-04-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769232	SCV000902785	likely benign	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172543	SCV003829146	likely benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318345	SCV004021997	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1
PreventionGenetics, part of Exact Sciences	RCV003974881	SCV004792821	likely benign	DSP-related disorder	2023-06-14	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).
CSER _CC_NCGL, University of Washington	RCV000291666	SCV000503539	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172543	SCV001741466	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038062	SCV001922144	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172543	SCV001930173	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172543	SCV001956188	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172543	SCV001964914	likely benign	not provided		no assertion criteria provided	clinical testing