ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2357+1G>A (rs111517471)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157417 SCV000199907 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2016-01-20 criteria provided, single submitter clinical testing The c.2489+1G>A variant in PKP2 has been reported in >25 ethnically diverse indi viduals with ARVC and segregated with disease in 4 affected relatives from 4 fam ilies (Gerull 2004, Baskin 2013, Dalal 2009, Dalal 2006, van Tintelen 2006, Cox 2011, Quarta 2011, Fressart 2010, Jordan 1985, Nakajima 2012, Palmisano 2011). T his variant has also been identified by our laboratory in 4 individuals (3 with ARVD/C and 1 with HCM) and segregated with disease in 2 affected relatives from 2 families. The c.2489+1G>A variant has been reported by other clinical laborato ries in ClinVar (Variation ID 6757) and has been identified in 4/126660 European and 2/24030 African chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs111517471). The c.2489+1G>A variant occur s in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. In sum mary, this variant meets criteria to be classified as pathogenic based upon segr egation studies, presence in multiple affected individuals, low frequency in the general population and the predicted impact to the protein.
Blueprint Genetics RCV000157417 SCV000207158 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-07-27 criteria provided, single submitter clinical testing
GeneDx RCV000183714 SCV000236192 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The c.2489+1 G>A pathogenic variant in the PKP2 gene has been published in several individuals with ARVC and has been observed in multiple individuals referred for cardiac genetic testing at GeneDx (Gerull et al., 2004; Dalal et al., 2006; van Tintelen et al., 2006; Fressart et al., 2010; Tan et al., 2010; Cox et al., 2011; Palmisano et al., 2011; Quarta et al., 2011; Nakajima et al., 2012; Walsh et al., 2017). It has also been shown to segregate with disease in multiple affected relatives from unrelated families, as reported in published literature and observed at GeneDx (Dalal et al., 2006; van Tintelen et al., 2006). Additionally, haplotype analysis by van Tintelen et al. (2006) suggests this variant may be a Dutch founder mutation. The c.2489+1 G>A variant is observed at a global allele frequency of 6/277168 (0.002%) alleles in large population cohorts, including 2/24030 (0.008%) alleles from individuals of African ancestry (Lek et al., 2016). This pathogenic variant destroys the canonical splice donor site in intron 12 and is predicted to cause abnormal gene splicing. The c.2489+1 G>A variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Moreover, other splice site variants in the PKP2 gene, including one affecting the same nucleotide (c.2489+1 G>T), have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014).
Invitae RCV000007149 SCV000638891 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2020-01-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the PKP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs111517471, ExAC 0.01%). This variant has been reported in the literature in many unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031616, 20031617, 21822014, 22214898). ClinVar contains an entry for this variant (Variation ID: 6757). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618114 SCV000734902 pathogenic Cardiovascular phenotype 2018-08-29 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000007149 SCV000743444 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000007149 SCV000744691 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183714 SCV000748005 pathogenic not provided 2017-07-17 criteria provided, single submitter clinical testing
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000714906 SCV000845660 pathogenic Arrhythmogenic ventricular cardiomyopathy 2017-08-21 criteria provided, single submitter clinical testing This variant has previously been reported in multiple patients with ARVC (Gerull et al. Nat Genet. 2004 Nov;36(11):1162-4; Dalal et al. J Am Coll Cardiol. 2006 Oct 3;48(7):1416-24; Nakajima et al. Circ J. 2012;76(3):737-43; Olfson et al. PLoS One. 2015 Sep 2;10(9):e0135193; Walsh et al. Genet Med. 2017 Feb;19(2):192-203; Xiong et al. Science. 2015 Jan 9;347(6218):1254806; Palmisano et al. Cardiology. 2011;119(1):47-53; Cox et al. Circulation. 2011 Jun 14;123(23):2690-700; Quarta et al. Circulation. 2011 Jun 14;123(23):2701-9; Tan et al. J Cardiovasc Transl Res. 2010 Dec;3(6):663-73; Fressart et al. Europace. 2010 Jun;12(6):861-8; den Haan et al. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35; Bhuiyan et al. Circ Cardiovasc Genet. 2009 Oct;2(5):418-27; Dalal et al. J Am Coll Cardiol. 2009 Apr 14;53(15):1289-99; van Tintelen et al. Circulation. 2006;113(13):1650-8; Dalal et al. Circulation. 2006 Apr 4;113(13):1641-9; ClinVar variation ID 6757). It has been detected at a very low allele frequency in control populations (6/277168; 0.0022%; gnomAD database). Algorithms predict this variant will disrupt the canonical donor splice site and lead to an aberrant splice transcript and premature termination of translation, leading to an abnormal or absent protein. Premature truncation of PKP2 is a known disease mechanism in ARVC (Gerull et al Nat Genet. 2004 Nov;36(11):1162).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000999576 SCV001156277 pathogenic Aborted sudden cardiac death 2018-02-09 criteria provided, single submitter research PKP2 c.2489+1G>A has been previously reported in multiple ARVC probands (Gerull B, et al., 2004; Dalal D, et al., 2006; van Tintelen JP, et al., 2006; Watkins DA, et al., 2009; Fressart V, et al., 2010; van der Werf C, et al., 2010; Tan BY, et al., 2010; Quarta G, et al., 2011; Palmisano BT, et al., 2011; Cox MG, et al., 2011; Nakajima T et al., 2012; Baskin B, et al., 2013) and in at least one family, has been found to segregate to an affected family member (Dalal D, et al., 2006). We identified this variant in a proband who presented with aborted cardiac arrest, but has no cardiac features suggestive of ARVC. The proband has a family history of sudden death however segregation was not possible. The variant is present at a low frequency in the Genome Aggregation Database (MAF=0.00002; http://gnomad.broadinstitute.org/). In summary, the variant has been reported in numerous ARVC cases, is rare in the general population and PKP2 loss of function variants are an established cause of disease, therefore we classify PKP2 c.2489+1G>A as "pathogenic".
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171154 SCV001333838 pathogenic Cardiomyopathy 2017-11-29 criteria provided, single submitter clinical testing
Color RCV001171154 SCV001343128 pathogenic Cardiomyopathy 2019-01-28 criteria provided, single submitter clinical testing
OMIM RCV000007149 SCV000027345 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2004-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183714 SCV000280414 pathogenic not provided 2014-03-27 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. IVS12+1 G>A (c.2489+1 G>A) in the PKP2 gene Mutations in the PKP2 gene have been reported in at least 11% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). This is a variant that we can have high confidence causes ARVC. It has been reported previously in multiple patients with ARVC, from multiple ethnicities, and also in multiple unrelated individuals tested for ARVC at GeneDx, according to their report. It is a splice-site variant that destroys the canonical splice donor site in intron 12. It is expected to cause abnormal gene splicing, which may lead to protein truncation or absence of protein due to mRNA decay. At least 24 patients with this specific variant have been published in the literature. Gerull et al. (2004) identified it in 1 ARVC proband of Western European descent. Dalal et al. (2006) found it in 3 unrelated patients with ARVC from the Johns Hopkins registry– and den Haan et al. (2009) added 1 more North American patient to this group. Age at first symptom for these patients ranged from 22-51 years. [Reports by Dalal et al. (2009) and Tan et al. (2010) appear to refer to these same patients.] van Tintelen et al. (2006) found the variant in 3 unrelated Dutch Caucasian individuals with ARVC. Of the cohort studied, patients with this variant had the youngest age of onset (ages 17, 17, and 20). Haplotype analysis indicated that it may be a founder mutation. One patient also carried a missense variant in PKP2: p.Glu62Lys. [Bhuiyan et al. (2009) appears to refer to the same patients as the van Tintelen et al. study.] Cox et al. 2011 identified it in 6 index patients (it is unclear how many of these were in the prior paper by van Tintelen et al. 2006 from the same group); two patients also carried a missense variant in DSG2 or JUP. Two 16-year-old males in one of these families suffered sudden cardiac death. Wlodarska et al. 2008 saw it in at least one Polish patient. Fressart et al. (2010) found it in 3 unrelated individuals recruited in France and/or Switzerland. Quarta et al. (2011) saw it in one patient referred to a center in London. Palmisano et al. (2011) studied a young male athlete with aborted cardiac arrest at age 21 and his affected but asymptomatic father, who both carried this variant and also a DSC2 I109M variant. The family’s ancestry may have been from Iran. Nakajima et al. (2012) found the variant in a Japanese patient who also carried the PKP2 variant D812N (in trans, one inherited from each of his unaffected parents). He had his first cardiac syncopal event (VT) at age 11 and was diagnosed at age 20. Baskin et al. (2013) found the variant in 2 ARVC patients tested in Canada. Bao et al. (2013) found it in 4 Chinese patients with ARVC. There is only very weak segregation data available: van Tintelen et al. (2006) saw it segregate in 2 affected family members. Palmisano et al. (2011) saw it segregate in an affected father and son. In total the variant has not been seen in more than 8500 presumably unaffected individuals, including 2000 controls and ~6500 individuals from population datasets. Dalal et al. (2006) did not find it in 200 controls (ancestry not specified); van Tintelen et al. (2006), 150 Caucasian controls; Wlodarska et al. (2008), 100 Caucasian controls; Fressart et al. (2010), 300 Caucasian controls; Cox et al. (2011), 200 Dutch Caucasian controls; Quarta et al. (2011), 300 ethnically-matched controls; Nakajima et al. (2012), 80 Japanese controls; Baskin et al. (2013), 427 controls; Bao et al. (2013), 300 Chinese(?) controls. It is not seen in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Chinese. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of March 27, 2014).

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