ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2299C>A (p.Arg767Ser) (rs139734328)

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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 RCV000190558 SCV000051588 benign Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038209 SCV000061877 likely benign not specified 2017-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000038209 SCV000236190 uncertain significance not specified 2017-02-07 criteria provided, single submitter clinical testing p.Arg811Ser (CGC>AGC): c.2431 C>A in exon 12 of the PKP2 gene (NM_004572.3). The R811S variant of uncertain significance in the PKP2 gene has been reported previously in individuals with ARVC (Tan et al., 2010; Klauke et al., 2010; Alcalde et al., 2014), including one individual who harbored a known pathogenic variant in another ARVC-related gene (Fressar et al., 2010). However, this variant was identified in healthy control individuals (Tan et al., 2010) and the NHLBI Exome Sequencing Project and the 1000 Genomes Project identified the R811S variant with a frequency of 0.06%-0.2% of alleles of individuals of European and Mixed American ancestry, indicating it may be a rare benign variant in these populations. Additionally, the Exome Aggregation Consortium includes one individual of European ancestry who is homozygous for this variant. Nevertheless, the R811S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.The variant is found in ARVC,CARDIOMYOPATHY,ARRHYTHMIA panel(s).
Ambry Genetics RCV000244829 SCV000318609 likely benign Cardiovascular phenotype 2018-10-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000458904 SCV000557321 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000458904 SCV000743445 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-06-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000458904 SCV000744692 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Color RCV000776101 SCV000910922 likely benign Cardiomyopathy 2018-04-10 criteria provided, single submitter clinical testing
Mendelics RCV000458904 SCV001138676 benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000858416 SCV001148690 likely benign not provided 2017-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000458904 SCV001272955 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-08-02 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV000038209 SCV001362101 likely benign not specified 2019-11-11 criteria provided, single submitter clinical testing Variant summary: PKP2 c.2431C>A (p.Arg811Ser) results in a non-conservative amino acid change in 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 0.0009 in 253 076 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is benign. The variant, c.2431C>A, has been reported in the literature in individuals affected with ARVD and other cardiological phenotypes (Fressart_2010, Klauke_2010, Tan_2010, Bottillo_2016, Proost_2017, Chua_2018, Sahlin_2019), however without strong evidence for pathogenicity (i.e. lack of co-segregation data). Therefore these reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. In addition, co-occurrence with another pathogenic variant has been reported (MYBPC3 c.3192dup (p.Lys1065fsX12); Bottillo_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (6x) or VUS (1x). Based on the evidence outlined above, the variant was classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148730 SCV000190464 uncertain significance Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2014-06-01 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000458904 SCV000733154 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing

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