ClinVar Genomic variation as it relates to human health

The c.148_151delACAG (p.Thr50Serfs*61) variant in the PKP2 gene is predicted to introduce a premature translational termination codon. It has been reported in multiple unrelated patients and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID: 15489853, 16567567, 17010805, 20129281, 20400443]. This c.148_151delACAG (p.Thr50Serfs*61) variant in the PKP2 gene is therefore classified as pathogenic.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP4.

Variant summary: PKP2 c.148_151delACAG (p.Thr50SerfsX61) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 212256 control chromosomes. c.148_151delACAG has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Te Riele_2017). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000045028, PMID:15489853). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Reported in numerous probands with ARVC and found to segregate with disease with multiple relatives from several families (Gerull et al., 2004; Dalal et al., 2006; van Tintelen et al., 2006; Bauce et al., 2010; Fressart et al., 2010; Xu et al., 2010; Cox et al., 2011; Baskin et al., 2013; Caspi et al., 2013; Philips et al., 2014; Walsh et al., 2017; Asatryan et al., 2019; Hermida et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Functional studies have demonstrated that this variant results in reduced PKP2 mRNA and protein levels (Caspi et al., 2013); Reported in ClinVar as pathogenic (ClinVar Variant ID# 45028; ClinVar); This variant is associated with the following publications: (PMID: 23810883, 32183154, 20031616, 20400443, 30975432, 24585727, 20129281, 21606396, 23347029, 17010805, 15489853, 20152563, 16567567, 23812740, 21606390, 27532257, 30161220, 19302745, 16549640, 16415378, 29606362, 30790397, 31514951, 31447099, 25825460, 32372669, 31386562, 31402444, 33232181, 32600061, 33087929, 24200905, 30847666)

A Heterozygous Frameshift variant c.148_151delACAG in Exon 1 of the PKP2 gene that results in the amino acid substitution p.Thr50fs*61 was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The reference base is not conserved across the species and in-silico predictions by Polyphen, SIFT are tolerated. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 45028]. The observed variation has previously been reported for arrhythmogenic right ventricular cardiomyopathy by Costa, Sarah, et al., 2021. For these reasons this variant has been classified as Pathogenic.

The c.148_151del variant identified in PKP2 has previously been reported in multiple individuals with ARVC/D [PMID: 15489853, 33232181, 33087929,32183154, 16415378, 16567567, 17010805, 19302745, 20400443, 23347029], and it has been deposited in ClinVar as Pathogenic by multiple submitters [ClinVar ID:45028]. The c.148_151del variant has been observed in 7 alleles with no homozygotes in the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.148_151del variant is located in the first exon of this 14-exongene and predicted to cause a frameshift in the open reading frame (p.(Thr50fs)). Functional studies have demonstrated that this variant results in reduced PKP2mRNA and protein levels [PMID: 24200905]. There are also multiple upstream loss-of-function variants reported in the literature in individuals with ARVC/D [PMID:28349240]. Based on available evidence this c.148_151del (p.(Thr50fs)) variant identified in PKP2 is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Thr50Serfs*61) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16415378, 16567567, 17010805, 19302745, 20400443, 23347029, 24200905). It has also been observed to segregate with disease in related individuals. This variant is also known as c.145_148delCAGA. ClinVar contains an entry for this variant (Variation ID: 45028). For these reasons, this variant has been classified as Pathogenic.

This variant (also known as c.145_148delCAGA) deletes 4 nucleotides in exon 1 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16415378, 16567567, 17010805, 19302745, 20400443, 23347029, 24200905). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

This sequence change in PKP2 is a frameshift variant predicted to cause a premature stop codon, p.(Thr50Serfs*61), in biologically relevant exon 2/13 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.007% (3/44,204 alleles) in the East Asian population. This is a recurrent variant reported in multiple individuals with arrhythmogenic cardiomyopathy (ACM; PMID: 34191271, 28588093, 25820315, 27532257). The variant has been reported to segregate with ACM in multiple families (PMID: 17010805, 20129281). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Moderate.

The p.Thr50SerfsX61 variant in PKP2 (also described as c.145_148delCAGA; c.144_148delCAGA; p.S50fsX110; p.Thr50_Val51SerfsX60 in the literature) has been reported in >20 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC; Gerull 2004 PMID: 15489853, Syrris 2006 PMID: 16415378, Dalal 2006a PMID: 16549640, van Tintelen 2006 PMID: 16567567, Dalal 2006b PMID: 17010805, Wu 2009 PMID: 19302745, Bhuiyan 2009 PMID: 20031616, Bauce 2010 PMID: 20129281, Xu 2010 PMID: 20152563, Fressart 2010 PMID: 20400443, Cox 2011 PMID: 21606396, Tisma-Dupanovic 2013 PMID: 23347029, Baskin 2013 PMID: 23812740, Caspi 2013 PMID: 24200905, Philips 2014 PMID: 24585727, Walsh 2017 PMID: 27532257, Te Riele 2017 PMID: 28069705, van Lint 2019 PMID: 31386562, Smith 2020 PMID: 32372669, Hirono 2020 PMID: 32600061, Stava 2022 PMID: 35653365, Goudal 2022 PMID: 35819174, LMM data), and in 1 individual with dilated cardiomyopathy (DCM; Gigli 2019 PMID: 31514951), and has also been reported by other clinical laboratories in ClinVar (Variation ID 45028). This variant segregated with disease in >7 individuals across multiple families (Dalal 2006b PMID: 17010805, Wu 2009 PMID: 19302745, Bauce 2010 PMID: 20129281, Smith 2020 PMID: 32372669, Stava 2022 PMID: 35653365, LMM data), but it is also present in several reportedly unaffected relatives (age range: 52-74 , indicating possible reduced penetrance (Syrris 2006 PMID: 16415378, Wu 2009 PMID: 19302745, Bauce 2010 PMID: 20129281, Perrin 2013 PMID: 23810883, LMM data). Additionally, this variant has been identified in 0.006% (1/15282) of Latino/Admixed American and 0.003% (2/67984) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 50 and leads to a premature termination codon 61 amino acids downstream and is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant ARVC. Additionally, an in vitro functional study using human induced pluripotent stem cell derived cardiomyocytes from an ARVC patient with the variant provide some evidence that this variant impacts protein function by disrupting desmosomal function and morphology and potentially recapitulating the ARVC phenotype in the culture dish (Caspi 2013 PMID: 24200905). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS4, PP1_strong, PM2_Supporting, PVS1, PS3_Supporting.

The c.148_151delACAG pathogenic mutation, located in coding exon 1 of the PKP2 gene, results from a deletion of 4 nucleotides at nucleotide positions 148 to 151, causing a translational frameshift with a predicted alternate stop codon (p.T50Sfs*61). This alteration, alternatively reported as p.S50fsX110, has been reported in multiple subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) and has been shown to segregate with disease in at least one family (Gerull B et al. Nat. Genet., 2004 Nov;36:1162-4; Dalal D et al. J. Am. Coll. Cardiol., 2006 Oct;48:1416-24; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Fressart V et al. Europace, 2010 Jun;12:861-8; Baskin B et al. Hum. Genet., 2013 Nov;132:1245-52; Philips B et al. Circ Arrhythm Electrophysiol, 2014 Apr;7:230-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Hermida A et al. Eur. J. Heart Fail., 2019 Jun;21:792-800; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). This variant has also been identified in a cohort of individuals with dilated cardiomyopathy (Gigli M et al. J. Am. Coll. Cardiol., 2019 Sep;74:1480-1490). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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 cardiomyopathy (ARVC) (MIM#609040). On the other hand, dominant-negative is the proposed mechanism for missense variants in this gene (PMID: 23183494, 24967631). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 17010805, 23183494). (I) 0201 - Variant 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). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PP4, PM2, PS4, PVS1

The PKP2 c.148_151delACAG variant is predicted to result in a frameshift and premature protein termination (p.Thr50Serfs*61). This variant is alternatively referred to as (c.145_148del; S50fx100, T50SfsX60) in literature. It has been reported in several individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (see for example, Table 1, Gerull et al. 2004. PubMed ID: 15489853; Bauce et al. 2009. PubMed ID: 20129281; Table 2, Dalal et al. 2006. PubMed ID: 17010805; Table S2, Hermida et al. 2019. PubMed ID: 30790397). This variant has also been reported in an individual with left ventricular noncompaction (LVNC) (Table 2, Hirono et al. 2020. PubMed ID: 32183154) and a survivor of sudden cardiac arrest (Table 2, Asatryan et al. 2019. PubMed ID: 30975432). This variant has been reported in asymptomatic or mildly affected family members, which may be related to age of disease presentation (Bauce et al. 2009. PubMed ID: 20129281; Table 2, Dalal et al. 2006. PubMed ID: 17010805). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKP2 are expected to be pathogenic. This variant is interpreted as pathogenic.