Submissions for variant NM_004415.4(DSP):c.6208G>A (p.Asp2070Asn)

gnomAD frequency: 0.00290  dbSNP: rs41302885

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172544	SCV000051389	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038072	SCV000061738	likely benign	not specified	2015-03-24	criteria provided, single submitter	clinical testing	p.Asp2070Asn in exon 24 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (393/65968) of European chromo somes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs41302885).
Eurofins Ntd Llc (ga)	RCV000038072	SCV000228149	likely benign	not specified	2014-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000172544	SCV000233551	benign	not provided	2019-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25661095, 26073755, 26743238, 26498160, 24503780, 30972196, 31028937, 33232181)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172544	SCV000280846	likely benign	not provided	2015-09-29	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085925	SCV000288545	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244881	SCV000318901	likely benign	Cardiovascular phenotype	2018-09-21	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	RCV000415621	SCV000465158	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). 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.
Illumina Laboratory Services, Illumina	RCV000367032	SCV000465160	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.
Illumina Laboratory Services, Illumina	RCV000274742	SCV000465161	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000038072	SCV000740335	benign	not specified	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776062	SCV000910710	likely benign	Cardiomyopathy	2018-03-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172544	SCV001154652	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	DSP: BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776062	SCV001332691	benign	Cardiomyopathy	2018-01-29	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000038072	SCV001422580	likely benign	not specified	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Asp2070Asn variant in DSP has been reported in 1 individual with arrhythmogenic cardiomyopathy (ACM), 2 with dilated cardiomyopathy (DCM), 1 with idiopathic ventricular fibrillation, and 1 suspected to have a genetic cardiovascular disease (PMID: 30820396, 25661095, 24503780, 26743238), and has been identified in 0.7910% (82/10366) of Ashkenazi Jewish chromosomes, 0.5636% (725/128630) of European (non-Finnish) chromosomes, and 0.5166% (183/35426) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs41302885). At least 3 affected individuals with this variant have an alternative molecular basis for DCM or ACM, suggesting that this variant may not be pathogenic (PMID: 24503780, 30820396; Variation ID: 45063). This variant has also been reported as benign, likely benign, and a VUS in ClinVar (Variation ID: 44936). The Aspartate (Asp) at position 2070 is highly conserved in mammals and evolutionary distant species, but one mammal (Wallaby) carries a Asparagine (Asn), supporting that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP5 (Richards 2015).
Genetics and Genomics Program, Sidra Medicine	RCV001293067	SCV001434049	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172544	SCV001473066	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038072	SCV000280093	uncertain significance	not specified	2014-03-26	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 information regarding prevalence in the control population, it is likely this variant is too common to contribute significantly to disease. There are no publications associating this variant with ARVC. The ARVC variant database lists this variant as ‘nonpathogenic’ (http://www.arvcdatabase.info). This is a semi conservative amino acid change with a negatively charged aspartic acid replaced with a neutral asparagine. Aspartic acid is semi conserved at residue 2070 in the DSP gene. In silico analysis (PolyPhen 2) predicts the amino acid change to be probably damaging to protein structure/function. There are no reported missense variants in nearby residues. In total the variant has been seen in 46 of 7,160 laboratory controls, published controls and individuals from publicly available population datasets. This variant is found in 39 of 4,280 (0.91%) European American individuals and 4 of 2,201 (0.81%) African American individuals listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 11/26/13). This variant is listed in dbSNP (rs41302885). Kapplinger et al (2011) did not observe the variant in 427 presumably healthy individuals that they studied.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415621	SCV000493737	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2015-06-04	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172544	SCV001798653	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038072	SCV001923201	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172544	SCV001930820	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038072	SCV001956719	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172544	SCV001966139	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003974882	SCV004789960	benign	DSP-related disorder	2019-10-30	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).