rs193922674

Variant names:

• chr12-32802557-C-G
• rs193922674
• NM_001005242.3:c.2014-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.2014-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000768 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: PKP2 NM_001005242.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:37
• Conservation: PhyloP100: 5.51

Genes affected

PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 12-32802557-C-G is Pathogenic according to our data. Variant chr12-32802557-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32802557-C-G is described in Lovd as [Pathogenic]. Variant chr12-32802557-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.2014-1G>C		splice_acceptor_variant, intron_variant	Intron 9 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2014-1G>C		splice_acceptor_variant, intron_variant	Intron 9 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251262 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461542 Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54 AN XY: 727110

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33478

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53352

Gnomad4 NFE exome AF: 0.000104 AC: 116 AN: 1111750

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000587907 AN: 0.0000587907

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:22

May 21, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 01, 2021

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 08, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 10 of the PKP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs193922674, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 24784157, 25087486, 27335691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6756). Studies have shown that disruption of this splice site results in altered splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15489853, 25087486). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2016

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The PKP2 c.2146-1G>C variant has been reported in multiple ARVC probands (see literature), and has been found to segregate with disease in a few families (Dalal D et al., 2006; Groeneweg JA, et al., 2014; Svensson et al., 2016). The variant affects a canonical splice acceptor site of intron 10 and was found to result in exon 11 skipping and consequently a shift in the reading frame (Groeneweg JA, et al., 2014). The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.00005; http://exac.broadinstitute.org/). We identified this variant in 3 male ARVC probands. 2/3 probands have no family history of disease. The other proband has family history of ARVC and sudden death, and passed away from a cardiac arrest at young age. In summary, based on LOF variants in PKP2 being an established mechanism of ARVC, multiple ARVC probands reported with the variant, cosegregation with disease and rarity in the general population, we classify PKP2 c.2146-1G>C as a "pathogenic" variant. -

Nov 09, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 28, 2024

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Str PS4_Str PP1_Mod PM2 -

Sep 28, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4 -

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (ARVD/ARVC) (MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (ClinVar, PMID: 17010805, PMID: 23183494). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR showed skipping of exon 11, resulting in a frameshift, which is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction) (PMID: 25087486). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other loss of function variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic in multiple families with ARVC (ClinVar, PMID: 27335691). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 21, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:6

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 28, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2146-1G>C variant in PKP2 has been reported in >30 individuals with ARVC (Gerull 2004 PMID: 15489853, Syrris 2006 PMID: 16415378, Dalal 2006 PMID: 16549640, Watkins 2009 PMID: 19880068, den Haan 2009 PMID: 20031617, Asimaki 2009 PMID: 19279339, La Gerche 2010 PMID: 20525856, Fressart 2010 PMID: 20400443, Borahona-Dussault 2010 PMID: 19863551, Cox 2011 PMID: 21606396, Baskin 2013 PMID: 23812740, Philips 2014 PMID: 24585727, Svensson 2016 PMID: 27335691, Walsh 2017 PMID: 27532257, LMM data) and segregated with disease in at least 8 affected relatives from 5 families (Groeneweg 2014 PMID: 25087486, Svensson 2016 PMID: 27335691, LMM data). However, it has also been observed in multiple unaffected individuals over the age of 50, which suggests that penetrance may be reduced (Perrin 2013 PMID: 23810883, Svensson 2016 PMID: 27335691, LMM data). It has also been identified in 0.007% (9/129048) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The c.2146-1G>C variant has been shown to cause skipping of exon 11, resulting in a frameshift (p.Pro716fs) and premature termination 32 amino acids downstream, ultimately leading to a marked reduction of PKP2 protein in the myocardium (Gerull 2004 PMID: 15489853, Asimaki 2009 PMID: 19279339, Groeneweg 2014 PMID: 25087486). Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner; however, it should be noted that penetrance may be reduced. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting, PP1_Moderate. -

Aug 26, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.2146-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing, specifically that the variant abolishes a 3' acceptor site. This prediction was confirmed by experimental evidence that demonstrated this variant affects mRNA splicing resulting in exon 11 skipping (Gerull_2004, Groeneweg_2014). The variant allele was found at a frequency of 3.2e-05 in 251262 control chromosomes (gnomAD). c.2146-1G>C has been reported in the literature in numerous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, including unrelated families where the variant co-segregated with the disease, though incomplete co-segregation was also observed suggesting somewhat reduced penetrance (Dalal_2006, Fressart_2010, Gerull_2004, Groeneweg_2014, Syrris_2006). These data indicate that the variant is very likely to be associated with disease. Immunohistochemical studies indicated marked reduction of the PKP2 protein level in a myocardium sample from an affected individual (Asimaki_2009). 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2146-1G>C of the PKP2 gene has been reported in numerous (>30) individuals affected with Arrhythmogenic Right Ventricular Cardiomyopathy (PMID: 15489853, 16415378, 16549640, 17010805, 18554203, 19279339, 19358943, 19880068, 20031617, 19863551). This variant was found to segregate with disease in several families (PMID: 27335691, 25087486). However, it has also been seen in multiple asymptomatic individuals, suggesting incomplete penetrance (PMID: 17010805, 18554203, 27335691, 23810883). Experimental evidences suggest that this variant causes skipping of exon 11, which results in a frameshift and premature termination codon, leading to severely reduced expression of the PKP2 protein (PMID: 15489853, 19279339, 25087486). Loss of function variants of PKP2 are known to be pathogenic (PMID: 23911551, 15489853). This variant is found to be rare (9/282670) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 6756). Therefore, the c.2146-1G>C variant in the PKP2 gene is classified as pathogenic. -

not provided Pathogenic:5

Apr 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals with ARVC referred for testing at GeneDx and in published literature (Gerull et al., 2004; Syrris et al., 2006; Dalal et al., 2006; den Haan et al., 2009; Watkins et al., 2009; Fressart et al., 2010; Tan et al., 2010; Perrin et al., 2013; Kant et al., 2016; Svensson et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional studies revealed c.2146-1 G>C causes skipping of exon 11, resulting in a shift in reading frame (Groeneweg et al., 2014); This variant is associated with the following publications: (PMID: 20525856, 20152563, 16415378, 19279339, 30790397, 30868567, 21606390, 20864495, 25525159, 19880068, 20857253, 15489853, 17010805, 18554203, 20031617, 20400443, 27335691, 26676851, 24784157, 23810883, 28518168, 28253841, 29997227, 27532257, 24585727, 23812740, 21636032, 21606396, 28177452, 26264440, 25351510, 19863551, 19302745, 29253866, 30998997, 30677492, 19955750, 16549640, 31737537, 31447099, 25825460, 32372669, 31386562, 31402444, 25087486, 32522011, 33232181, 33238575, 32686758, 34135346, 33087929) -

Oct 05, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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 (Ge -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2: PVS1, PS4:Moderate -

Cardiomyopathy Pathogenic:2

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the -1 position of intron 10 splice acceptor site of the PKP2 gene. Functional RNA studies have shown that this variant causes skipping of exon 11 and 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, 35579515, 35653365, 37418234) and has been shown to segregate with disease in multiple families (PMID: 25087486, 27335691). This variant has been identified in 9/282670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic. -

Mar 10, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKP2-related disorder Pathogenic:1

Jan 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKP2 c.2146-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is also referred to as c.2014-1G>C using an alternate transcript (NM_001005242.3). This variant has been reported to be causative for arrhythmogenic right ventricular dysplasia (ARVD; Gerull et al. 2004. PubMed ID: 15489853; La Gerche et al. 2010. PubMed ID: 20525856; Perrin et al. 2013. PubMed ID: 23810883; OMIM #609040). In ClinVar, this variant is interpreted as pathogenic by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6756/). Furthermore, protein truncating variants up and downstream of this variant have been reported to be causative for ARVD (Gerull et al. 2004. PubMed ID: 15489853; Bao et al. 2013. PubMed ID: 24125834; Walsh et al. 2017. PubMed ID: 27532257). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2146-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 11 of the PKP2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (9/282670) total alleles studied. The highest observed frequency was 0.007% (9/129048) of European (non-Finnish) alleles. This variant has been observed in numerous unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was shown to segregate with disease in multiple families, though penetrance and expressivity were variable (Gerull, 2004; Dalal, 2006; Svensson, 2016). This nucleotide position is highly conserved in available vertebrate species. Functional studies on mRNA demonstrated that this mutation results in exon 11 skipping (Groeneweg, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.93	D
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922674; hg19: chr12-32955491;