Submissions for variant NM_004415.4(DSP):c.88G>A (p.Val30Met)

gnomAD frequency: 0.00094  dbSNP: rs121912998

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000029685	SCV000051381	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038118	SCV000052337	benign	not specified	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: DSP c.88G>A (p.Val30Met) results in a conservative amino acid change in 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 0.0016 in 212604 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.88G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Yang_2006, Bauce_2010, Xu_2010, Rasmussen_2013, Rasmussen_2013, Bhonsale_2013, Rigato_2013). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Rasmussen_2012). Fourteen 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 (Benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038118	SCV000061784	likely benign	not specified	2015-04-03	criteria provided, single submitter	clinical testing	p.Val30Met in exon 1 of DSP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including several primates, have a methionine (Met) at this position. This strongly argues against a disease causing role, though a modifyin g effect cannot be excluded. In addition, it has been identified in 0.6% (57/99 98) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs12192998). Of note, this variant has been publ ished by several studies (http://arvcdatabase.info/), though the data provided b y these studies is uninformative.
Eurofins Ntd Llc (ga)	RCV000724208	SCV000224441	uncertain significance	not provided	2015-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000724208	SCV000233655	likely benign	not provided	2020-08-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32268277, 31028938, 25637381, 16917092, 20152563, 21636032, 23137101, 23671136, 24070718, 20129281, 23861362, 26656175, 27153395, 26332594, 26569459, 23299917, 28473349, 25985138, 27435932, 28798025, 31019283, 31402444, 33232181)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000029685	SCV000257974	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-06-25	criteria provided, single submitter	clinical testing
Invitae	RCV001083215	SCV000288553	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	RCV000018340	SCV000464829	likely benign	Arrhythmogenic right ventricular dysplasia 8	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV000619218	SCV000735953	benign	Cardiovascular phenotype	2018-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000018340	SCV000883082	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000234980	SCV000910778	likely benign	Cardiomyopathy	2018-03-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164369	SCV001326492	likely benign	Woolly hair-skin fragility syndrome	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001164370	SCV001326493	likely benign	Lethal acantholytic epidermolysis bullosa	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000234980	SCV001333544	likely benign	Cardiomyopathy	2018-07-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000018340	SCV001440500	likely benign	Arrhythmogenic right ventricular dysplasia 8	2019-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724208	SCV001745920	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	DSP: BS2
PreventionGenetics, part of Exact Sciences	RCV003904847	SCV004723388	likely benign	DSP-related disorder	2022-09-12	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).
All of Us Research Program, National Institutes of Health	RCV003996108	SCV004822021	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000018340	SCV000038619	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2006-09-15	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000029685	SCV000190177	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234980	SCV000263110	pathogenic	Cardiomyopathy	2015-03-27	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038118	SCV000280098	uncertain significance	not specified	2014-02-06	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 data reviewed below, we consider this a variant of uncertain significance. This variant has been identified in multiple probands with ARVC and in one SCICD center patient with conduction system disease, biventricular dysfunction and a history of SCD. Yang et al (2006) first reported the variant in an individual with ARVC in a publication that only reports on DSP variants. In all other published cases this variant occurs with additional variants. Bauce et al (2010) identified an individual with ARVC and two DSP variants, p.Val30Met and p.Arg2541Lys. Each variant was detected in isolation in separate affected family members. Xu et al (2010) report a proband with the p.Val30Met variant as well as a nonsense and a missense variant in the PKP2 gene. This is a conservative amino acid change with the replacement on a nonpolar Valine with a nonpolar Methionine. Valine is not conserved across species and several species harbor a Methionine at this codon. In vitro studies reported by Yang et al (2006) showed that when this variant is present desmoplakin is trapped in the cytoplasm and fails to localize to the cell membrane. In total the variant has been seen in 21 of 9109 published controls and publicly available general population samples (as of 12/6/14). Across available publications the variant is absent in 1150 presumably healthy control individuals. However, more recently Kapplinger et al (2011) reported the variant in 1 of 427 presumably healthy individuals and the variant is reported in 16 of 4,269 European individuals in the NHLBI Exome Sequencing Project dataset and 0 of 2169 African American individuals (as of 2/6/14). It is also reported in dbSNP (rs 121912998), though this seems to point to the NHLBI data. It was also seen in 4 of 1094 individuals in the 1000 genomes low coverage data.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415109	SCV000492954	likely pathogenic	Right ventricular cardiomyopathy	2013-12-13	flagged submission	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198383	SCV001369295	likely pathogenic	Keratosis palmoplantaris striata 2	2016-01-01	flagged submission	clinical testing	This variant was classified as: Likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724208	SCV001741376	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000724208	SCV001798290	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038118	SCV001922801	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038118	SCV001931049	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038118	SCV001957805	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724208	SCV001973708	likely benign	not provided		no assertion criteria provided	clinical testing