Submissions for variant NM_001005242.3(PKP2):c.2014-1G>C

gnomAD frequency: 0.00003  dbSNP: rs193922674

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000054811	SCV000053029	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-08-26	criteria provided, single submitter	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000054811	SCV000061868	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2021-04-28	criteria provided, single submitter	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.
Blueprint Genetics	RCV000054811	SCV000207157	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2015-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000183771	SCV000236252	pathogenic	not provided	2022-04-29	criteria provided, single submitter	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)
Ambry Genetics	RCV000252055	SCV000319827	pathogenic	Cardiovascular phenotype	2024-01-12	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007148	SCV000545224	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2025-02-02	criteria provided, single submitter	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007148	SCV000677114	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2017-11-09	criteria provided, single submitter	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000007148	SCV000743451	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000007148	SCV000744696	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2017-05-31	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000007148	SCV000840038	pathogenic	Arrhythmogenic right ventricular dysplasia 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.
Fulgent Genetics, Fulgent Genetics	RCV000007148	SCV000893978	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771879	SCV000904636	pathogenic	Cardiomyopathy	2023-02-27	criteria provided, single submitter	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) 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000054811	SCV000987537	pathogenic	Arrhythmogenic right ventricular cardiomyopathy		criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007148	SCV000993586	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2018-09-21	criteria provided, single submitter	research
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000007148	SCV000996364	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2017-03-08	criteria provided, single submitter	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000007148	SCV001190256	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-05-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000183771	SCV001250082	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PS4:Moderate
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771879	SCV001333842	pathogenic	Cardiomyopathy	2022-03-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007148	SCV001440289	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2019-01-01	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000007148	SCV001760302	pathogenic	Arrhythmogenic right ventricular dysplasia 9		criteria provided, single submitter	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000007148	SCV002538614	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-05-01	criteria provided, single submitter	research
MGZ Medical Genetics Center	RCV000007148	SCV002579591	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-11-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000007148	SCV002764829	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-12-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000007148	SCV002767286	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-07-17	criteria provided, single submitter	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
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000007148	SCV004099191	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-09-28	criteria provided, single submitter	clinical testing	PVS1, PS4
All of Us Research Program, National Institutes of Health	RCV000054811	SCV004816512	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-09-03	criteria provided, single submitter	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.
Baylor Genetics	RCV000007148	SCV005049460	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-03-15	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000183771	SCV005197179	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000007148	SCV005374712	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-08-28	criteria provided, single submitter	clinical testing	PVS1_Str PS4_Str PP1_Mod PM2
OMIM	RCV000007148	SCV000027344	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2004-11-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000054811	SCV000190460	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
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).
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000007148	SCV000298150	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000007148	SCV000733159	pathogenic	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183771	SCV001953118	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000007148	SCV004171687	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-11-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924809	SCV004740948	pathogenic	PKP2-related disorder	2024-01-25	no assertion criteria provided	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.