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
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,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).
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.
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: 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 Clinical Services Laboratory,Illumina RCV000369032 SCV000465223 benign Skin fragility-woolly hair-palmoplantar keratoderma 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2020-12-04 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 Health, Inc RCV000771821 SCV000904526 benign Cardiomyopathy 2018-04-26 criteria provided, single submitter clinical testing
Mendelics RCV000987654 SCV001137054 benign Dilated cardiomyopathy with woolly hair and keratoderma 2019-05-28 criteria provided, single submitter clinical testing
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).

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