ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2146-1G>C (rs193922674)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252055 SCV000319827 pathogenic Cardiovascular phenotype 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,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
Blueprint Genetics RCV000054811 SCV000207157 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-05-04 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000054811 SCV000190460 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Color RCV000771879 SCV000904636 pathogenic Cardiomyopathy 2018-09-04 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant changes a single nucleotide in the canonical splice acceptor site in intron 10 of the PKP2 gene. Computational splicing tools suggest that this variant may have significant impact on RNA splicing. RNA studies with cells from arrhythmogenic cardiomyopathy patients have confirmed that this variant causes skipping of exon 11 and creates a premature truncation of the PKP2 gene product (PMID: 15489853, 25087486). This variant has been reported in over 40 individuals affected with arrhythmogenic cardiomyopathy (PMID: 15489853, 17010805, 17010805, 20031617, 20400443, 20857253, 23178689, 24784157, 25087486, 25087486, 27335691, 28523642) and has been shown to segregate with disease in multiple families (PMID: 25087486, 27335691). This variant has been identified in 10/277004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000007148 SCV000744696 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000007148 SCV000733159 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000007148 SCV000298150 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2016-05-01 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000007148 SCV000893978 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000183771 SCV000236252 pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing The c.2146-1 G>C pathogenic variant in the PKP2 gene has been reported in multiple individuals in association with ARVC (Gerull et al., 2004; Syrris et al., 2006; Dalal et al., 2006; den Haan et al., 2009; Fressart et al., 2010; Kant et al., 2016; Svensson et al., 2016). This variant is also reported to segregate with ARVC in multiple affected relatives in multiple families (Dalal et al., 2006; Svensson et al., 2016). Additionally, c.2146-1 G>C has been observed in several unrelated individuals referred for ARVC testing at GeneDx. The c.2146-1 G>C pathogenic variant destroys the canonical splice acceptor site in intron 10 and is expected to cause abnormal gene splicing. Functional studies using RT-PCR and Sanger sequencing revealed c.2146-1 G>C causes skipping of exon 11, resulting in a shift in reading frame (Groeneweg et al., 2014). Lastly, the c.2146-1 G>C variant is observed at a frequency of 10/126558 alleles (0.008%) in individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000007148 SCV000743451 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2014-10-08 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007148 SCV000677114 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-11-09 criteria provided, single submitter research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007148 SCV000993586 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-09-21 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000007148 SCV000840038 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-06-02 criteria provided, single submitter clinical testing This c.2146-1G>C variant has been reported in over 10 individuals with ARVD/cardiomyopathy with incomplete family segregation [PMID 15489853,17010805, 20525856, 24784157, 25087486]. This variant is located in the invariant splice acceptor site of intron 11. Functional assays showed that this change activates a cryptic splice acceptor site in intron 12 or, alternatively, another cryptic splice acceptor site in PKP2 exon 13 [PMID 15489853]. A variant affecting the same invariant splice site has also been reported in additional patients [PMID 19955750]. This variant has been detected in 6 heterozygous individuals from Europe (http://exac.broadinstitute.org/variant/12-32955491-C-G). It is thus classified as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000054811 SCV000053029 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-03 no assertion criteria provided clinical testing
Invitae RCV000007148 SCV000545224 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the PKP2 gene. It is expected to disrupt mRNA splicing and results in an absent or disrupted protein product. Truncating variants in PKP2 are known to be pathogenic (PMID: 15489853). This particular variant has been reported in many unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 24784157) and has been shown to segregate with the disease in many families (PMID: 25087486, 27335691). ClinVar contains an entry for this variant (Variation ID: 6756). Experimental studies have confirmed that this intronic change leads to splicing defects that creates a truncated PKP2 protein (PMID: 15489853, 25087486). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000054811 SCV000061868 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-10-10 criteria provided, single submitter clinical testing The c.2146-1G>C variant in PKP2 has been reported in >30 individuals with ARVC ( Gerull 2004, Syrris 2006, Dalal 2006, Wlodarska 2008, Watkins 2009, den Haan 200 9, Asimaki 2009, La Gerche 2010, Fressart 2010, Borahona-Dussault 2010, Cox 2011 , Baskin 2013, Philips 2014, Svensson 2016, Walsh 2017, LMM data, ClinVar Variat ion ID: 6756) and segregated with disease in at least 8 affected relatives from 5 families (Groeneweg 2014, Svensson 2016, LMM data). However, it has also been observed in multiple unaffected individuals over the age of 50, which suggests t hat penetrance may be reduced (Perrin 2013, Svensson 2016, LMM data). In additio n, this variant has been identified in 10/126558 European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1939 22674). Please note that for diseases with clinical variability or reduced penet rance, pathogenic variants may be present at a low frequency in the general popu lation. The c.2146-1G>C variant has been shown to cause skipping of exon 11, res ulting in a frameshift (p.Pro716fs) and premature termination 32 amino acids dow nstream, ultimately leading to a marked reduction of PKP2 protein in the myocard ium (Gerull 2004, Asimaki 2009, Groeneweg 2014). Heterozygous loss of PKP2 funct ion is an established disease mechanism in individuals with ARVC. In summary, th is variant meets criteria to be classified as pathogenic for ARVC in an autosoma l dominant manner; however, it should be noted that penetrance may be reduced. A CMG/AMP Criteria applied: PVS1, PS4, PM2, PP1_Moderate (Richards 2015).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000054811 SCV000987537 pathogenic Arrhythmogenic right ventricular cardiomyopathy criteria provided, single submitter clinical testing
OMIM RCV000007148 SCV000027344 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2004-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183771 SCV000280410 pathogenic not provided 2014-06-20 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. IVS10-1 G>C (c.2146-1 G>C) in intron 10 of the PKP2 gene (NM_004572.3) Given the strong case data and the fact that many splicing variants in PKP2 have been implicated in ARVC, we consider this variant very likely disease causing. The variant has been seen in at least 37 unrelated cases of ARVC (not including this patient's family). There is weak segregation data. Gerull et al (2004) observed the variant in two of 120 unrelated patients with ARVC of European decent who underwent sequencing of PKP2. Syrris et al (2006) observed the variant in one of 100 white patients from their British ARVC cohort (McKenna's group). Dalal et al (2006) observed the variant in 7 of 58 patients with ARVC in the Hopkins ARVC registry (note that 15 patients in the cohort were also enrolled in the national ARVC registry so may overlap with other reports). The same group reported in a separate paper on two of these families; in one family two affected invidiuals had the variant while in the other family two identical twins both had the variant. This group later reported on analysis of PKP2, DSG2, DSP, DSC2, and JUP in 82 patients with ARVC from the Hopkins registry; 10 patients have this variant, which appears to include the 7 previously reported (den Haan et al 2009). One of these patients had two additional desmosomal variant including a PKP2 missense previously reported with ARVC and a DSG2 missense that has been seen more frequently in both left and right sided cardiomyopathy than in controls and is hypothesized to be a modifier. The Hopkins cases appear to be included in several subsequent publications by their group (Tan et al 2010, Xu et al 2010). Wlodarska et al (2008) in an ESC abstract reported that they observed the variant in one of 42 patients with ARVC who underwent PKP2 screening by DHLPC and sequencing. Ancestry is not noted. Authors are from Italy and Poland. Watkins et al (2009) reported the variant in 1 of 50 unrelated ARVC paitents from their South African registry. Ancestry is not noted. Asimaki et al (2009) include an ARVC patient with this variant in their study on immunhistochemistry findings in ARVC. Unfortunately it is not noted how this patient was ascertained. Given this list of co-authors I suspect the case may come from the Hopkins cohort and thus overlaps with their reports (den Haan et al 2009, Dalal et al 2008). La Gerche et al (2010) analysed desmosomal genes in 47 endurance athletes with complex ventricular arrhythmias with right ventricular morphology. They observed this variant in two of those cases. Unfortunately individual phenotypic data is not provided. Two-thirds of athletes with a pathogenic variant met task force criteria for an ARVC diagnosis. Fressart et al (2010) sequenced five desmosomal genes in 135 patients with ARVC from their French and Swiss cohort and observed the variant in 7 unrelated patients. Borahona-Dussaul et al (2010) observed the variant in one of 23 patients with ARVC from their cohort in Montreal. Cox et al (2011) analyzed five desmosomal genes in their Dutch cohort of 149 ARVC patients and observed this variant in 7 patients. Baskin et al (2013) reported on sequencing of ARVC genes in 195 patients with suspected ARVC either seen in their clinic in Toronto or referred for genetic testing at their Toronto laboratory. Five patients had this variant. Perrin et al (2013) include a patient with this variant in their study on exercise testing in asymptomatic carriers; given the author list this patient was likely drawn from one of the previously published families. Nested RT-PCR on an ARVC patient with this variant showed an aberrant splicing product consistent with altered splicing (Gerull et al 2004). At least two dozen splice variants in this gene have been reported in association with ARVC (see http://www.arvcdatabase.info/). The majority of the disease-associated variants in PKP2 are splicing variants, frameshift, nonsense, or in-frame deletions. In one study 66 of 149 unrelated ARVC patients had such a variant (Cox et al 2011). In contrast, these variants are rare in the general population (Kapplinger et al 2011, NHLBI ESP). In total the variant has been seen in 2 of 7994 published controls and individuals from publicly available population datasets. The variant was reported online in 2 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of June 16th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other hypertrophic cardiomyopathy variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Note that a similar analysis is not available for ARVC genes. The variant is listed in dbSNP (rs193922674), with a submission from the above noted ESP data and Correlagen. Presumably the Correlagen data is from a variant found on clinical genetic testing. The variant was not observed in the following published control samples: 250 control individuals (Gerull et al 2004), 200 White control individuals (Syrris et al 2006), 200 control individuals (Dalal et al 2006, den Haan et al 2009), 100 control individuals (Wlodarska et al 2008), 241 controls (86 black African, 80 white, and 75 mixed ancestry; Watkins et al 2009), 300 Caucasians controls (Fressart et al 2010), 200 Caucasians (Cox et al 2011).

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