Submissions for variant NM_004415.4(DSP):c.1778A>G (p.Asn593Ser)

gnomAD frequency: 0.00055  dbSNP: rs34239595

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172534	SCV000051383	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038000	SCV000061666	benign	not specified	2018-03-12	criteria provided, single submitter	clinical testing	The p.Asn593Ser variant in exon 14 of DSP: This variant is not expected to have clinical significance because it has been identified in 0.1% (132/126514) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs34239595). In addition, it has been identified in severa l individuals who carried disease-causing variants in other genes (Rasmussen et al. 2013, LMM data) and computational prediction tools and conservation analysis suggest that this variant is unlikely to impact the protein. ACMG/AMP Criteria Applied: BA1; BP4; BP5.
GeneDx	RCV000172534	SCV000233585	likely benign	not provided	2023-05-16	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000246406	SCV000318048	likely benign	Cardiovascular phenotype	2020-10-08	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.
Illumina Laboratory Services, Illumina	RCV000311371	SCV000464907	likely benign	Lethal acantholytic epidermolysis bullosa	2019-09-30	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	RCV000370655	SCV000464908	likely benign	Woolly hair-skin fragility syndrome	2019-09-30	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	RCV001095237	SCV000464909	likely benign	Arrhythmogenic right ventricular dysplasia 8	2019-09-30	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV001086744	SCV000555784	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771809	SCV000904510	likely benign	Cardiomyopathy	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038000	SCV001363077	benign	not specified	2019-08-27	criteria provided, single submitter	clinical testing	Variant summary: DSP c.1778A>G (p.Asn593Ser) results in a conservative amino acid change located in the Desmoplakin, spectrin-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251294 control chromosomes, predominantly at a frequency of 0.0011 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 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1778A>G, has been reported in the literature in individuals affected with Cardiomyopathy and ARVC and these affected individuals had co-occurrences with other pathogenic variants (DSG2 c.137G>A, p.Arg46Gln (Rasmussen, 22013); TTN c.49511delG, p.Gly16504GlufsX12 (Pugh_2014)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as uncertain significance and three times as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001095237	SCV001440499	likely benign	Arrhythmogenic right ventricular dysplasia 8	2019-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914943	SCV004734840	likely benign	DSP-related condition	2024-03-02	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).
Blueprint Genetics	RCV000157188	SCV000206912	likely benign	Primary familial hypertrophic cardiomyopathy	2014-09-18	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000276099	SCV000503531	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	RCV000172534	SCV001743408	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172534	SCV001799144	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038000	SCV001925594	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172534	SCV001932801	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172534	SCV001952680	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172534	SCV001968233	likely benign	not provided		no assertion criteria provided	clinical testing