ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.7916G>A (p.Arg2639Gln) (rs116888866)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245063 SCV000318546 benign Cardiovascular phenotype 2016-09-26 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000262145 SCV000050860 benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000157210 SCV000206934 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-08-22 no assertion criteria provided clinical testing
Color RCV000771821 SCV000904526 benign Cardiomyopathy 2018-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000150581 SCV000233645 likely benign not specified 2017-11-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000312035 SCV000465222 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000369032 SCV000465223 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000262145 SCV000465224 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000319713 SCV000465225 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590413 SCV000698448 likely benign not provided 2017-05-29 criteria provided, single submitter clinical testing Variant summary: The DSP c.7916G>A (p.Arg2639Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in a plectin repeat domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the ExAC database and published reports in 126 of 122068 control chromosomes from all ethnicities, but was predominantly observed in the ExAC East Asian subpopulation at a frequency of 0.012167 (105/8630). This frequency is about 1217 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In the literature, the variant has been reported in multiple patients (East Asian) without strong evidence for pathogenicity (Sato_J Forensic Sci_2015; Bao_Circ Cardio Genet_2013; Zhao_Int J Legal Med_2016; Yu_JFMA_2008). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance, likely benign, and benign. Taken together, this variant is classified as likely benign until more evidence becomes available.
Invitae RCV000533074 SCV000641348 benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-05-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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).
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490472 SCV000267294 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-03-18 criteria provided, single submitter reference population
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).

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