Submissions for variant NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln)

gnomAD frequency: 0.00026  dbSNP: rs116888866

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000262145	SCV000050860	benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150581	SCV000197849	benign	not specified	2016-01-18	criteria provided, single submitter	clinical testing	Arg2639Gln in exon 24 of DSP: This variant is not expected to have clinical sign ificance because it has been identified in 1.2% (105/8630) of East Asian chromos omes by the by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org). In one study this variant has been identified in 4 Taiwanese individuals with ARVC, but was also identified in 1.3% (8/600) control chromosomes (Bao 201 3).
GeneDx	RCV001704081	SCV000233645	benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25693453, 20400443, 26585738, 24125834, 23911551, 20981092, 26332594, 18632414, 28471438, 32344918, 31402444)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490472	SCV000267294	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2016-03-18	criteria provided, single submitter	reference population
Ambry Genetics	RCV000245063	SCV000318546	benign	Cardiovascular phenotype	2016-09-26	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.
Illumina Laboratory Services, Illumina	RCV000369032	SCV000465223	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000490472	SCV000465224	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.
Illumina Laboratory Services, Illumina	RCV000319713	SCV000465225	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001086541	SCV000641348	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150581	SCV000698448	benign	not specified	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: DSP c.7916G>A (p.Arg2639Gln) results in a conservative amino acid change located in a plectin repeat (IPR001101) 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 0.00092 in 252300 control chromosomes, predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1100-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.7916G>A has been reported in the literature in East Asian individuals affected with Arrhythmia (Yu_2008, Bao_2013, Sato_2015, Zhao_2016), but it was also found in several controls (Bao_2013). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated a weak impact on the binding of the DSP C-terminus to the tested intermediate filaments (IF) proteins (Favre_2018). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000771821	SCV000904526	benign	Cardiomyopathy	2018-04-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000987654	SCV001137054	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771821	SCV003837792	benign	Cardiomyopathy	2021-10-20	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318355	SCV004022052	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP3, BS1
PreventionGenetics, part of Exact Sciences	RCV003945184	SCV004764573	likely benign	DSP-related disorder	2020-06-10	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	RCV000157210	SCV000206934	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-08-22	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000150581	SCV000280096	uncertain significance	not specified	2014-07-30	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. We consider this a variant of uncertain significance, probably benign, based on the weak case data, the mismatch with the phenotype, and that the variant is common in Asians. The variant has been seen in one Taiwanese patient with ARVC (Yu et al 2008) and one Chinese patient with ARVC (Bao et al 2013). However, it is also seen in Asian controls (reviewed below). In silico analysis predicts the variant to be probably damaging. The arginine at codon 2639 is conserved across species. The GeneDx report notes that another variant of uncertain significance has been reported in association with ARVC at this codon (p.Arg2639Trp), but that no other nearby variants are listed in HGMD. There are no nearby variants listed in www.arvcdatabase.info. In total the variant has been seen in 30 of 7179 published controls and individuals from publicly available population datasets, with ~5% of Asians in two different samples having the variant. There is no variation at codon 2639 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 23rd, 2014). Note that this dataset does not match the patient's ancestry (Japanese). Per the GeneDx report, the variant was observed in 14 of 279 Asian individuals in the 1000 genomes sample and 16 of 300 Chinese individuals studied by Bao et al (2013). The variant was not observed in 100 Tawainese individuals studied by Yu et al (2008).
Clinical Genetics, Academic Medical Center	RCV000150581	SCV001919134	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000150581	SCV001963172	benign	not specified		no assertion criteria provided	clinical testing