ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.88G>A (p.Val30Met) (rs121912998)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619218 SCV000735953 likely benign Cardiovascular phenotype 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
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
CSER_CC_NCGL; University of Washington Medical Center RCV000029685 SCV000190177 likely benign Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415109 SCV000492954 likely pathogenic Right ventricular cardiomyopathy 2013-12-13 criteria provided, single submitter clinical testing
Color RCV000234980 SCV000910778 likely benign Cardiomyopathy 2018-03-14 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000029685 SCV000257974 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-06-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724208 SCV000224441 uncertain significance not provided 2015-03-24 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000018340 SCV000883082 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-21 criteria provided, single submitter clinical testing
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234980 SCV000263110 pathogenic Cardiomyopathy 2015-03-27 no assertion criteria provided clinical testing
GeneDx RCV000038118 SCV000233655 likely benign not specified 2017-11-01 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 RCV000029685 SCV000464829 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000029685 SCV000052337 likely benign Arrhythmogenic right ventricular cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing
Invitae RCV000226589 SCV000288553 benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-01-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000018340 SCV000038619 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2006-09-15 no assertion criteria provided literature only
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.

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