ClinVar Miner

Submissions for variant NM_001005242.2(PKP2):c.148_151del (p.Thr50fs) (rs397516997)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157418 SCV000061833 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-04-27 criteria provided, single submitter clinical testing The p.Thr50fs variant in PKP2 has been reported in >20 individuals with ARVC (5 of these carried a second variant in either PKP2 or DSG2) and was absent from at least 3100 control chromosomes across multiple studies (Gerull 2004, Syrris, 20 06, Dalal 2006a, Van Tintelen 2006, Wu 2009, Bauce 2010, Fressart 2010, Xu 2010, Quarta 2011, Cox 2011, Tisma-Dupanovic 2013, Baskin 2013, Caspi 2013, Philips 2 014, LMM data; alternate nomenclature includes: 145_148delCAGA; 144_148delCAGA; S50fsX110; Thr50_Val51SerfsX60). This variant segregated with disease in 5 affec ted family members across 4 families (Dalal 2006b, Wu 2009, Bauce 2010, LMM data ), but it is also present in several asymptomatic individuals, indicating reduce d penetrance (Syrris 2006, Wu 2009, Xu 2010, Bauce 2010, LMM data). It has not b een identified in large population studies, although the ability of these studie s to identify indels is limited. This variant is predicted to cause a frameshift , which alters the protein's amino acid sequence beginning at codon 50 and leads to a premature stop codon 61 amino acids downstream. This alteration is then pr edicted to lead to a truncated or absent protein. In summary, the p.Thr50fs vari ant meets criteria to be classified as pathogenic for autosomal dominant ARVC wi th reduced penetrance.
GeneDx RCV000183796 SCV000236277 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The c.148_151delACAG pathogenic variant in the PKP2 gene has been previously reported multiple times (occasionally using alternate nomenclature) in association with ARVC/D (Gerull et al., 2004; Dalal et al., 2006; van Tintelen et al., 2006; Bhuiyan et al., 2009; Bauce et al., 2010; Fressart et al., 2010; Xu et al., 2010; Cox et al., 2011; Quarta et al., 2011; Baskin et al., 2013; Caspi et al., 2013; Tisma-Dupanovic et al., 2013; Philips et al., 2014). Bauce et al. (2010) identified this variant in a proband with ARVC/D and it was observed to segregate with disease in several affected maternal relatives. This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx.This variant causes a shift in reading frame starting at at codon threonine 50, changing it to a serine, and creating a premature stop codon at position 61 of the new reading frame, denoted p.Thr50SerfsX61. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Caspi et al. (2013) demonstrated a reduction in mRNA levels of PKP2 in cells from a patient with ARVC who harbored this variant, likely resulting from a nonsense-mediated mRNA decay mechanism. In addition, researchers identified marked desmosomal abnormalities and the accumulation of lipid droplets in several of the cells (Caspi et al., 2013). Other downstream frameshift variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC/D (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.148_151delACAG variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000228638 SCV000288591 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-23 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 1 of the PKP2 mRNA (c.148_151delACAG), causing a frameshift at codon 50. This creates a premature translational stop signal (p.Thr50Serfs*61) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic. This particular variant has been reported in individuals and families affected with arrythmogenic right ventricular cardiomyopathy, and has been shown to segregate with the disease in one family (PMID: 15489853, 16415378, 16567567, 17010805, 19302745, 20400443, 23347029, 24200905). This variant is also known as c.145_148delCAGA in the literature. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769400 SCV000900792 pathogenic Cardiomyopathy 2017-08-09 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183796 SCV000987493 pathogenic not provided criteria provided, single submitter clinical testing
Color RCV000769400 SCV001343927 pathogenic Cardiomyopathy 2019-11-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197242 SCV001367879 pathogenic Palpitations; Right ventricular cardiomyopathy; Reduced ejection fraction; Clinodactyly 2019-01-04 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in heterozygous state.
Blueprint Genetics RCV000157418 SCV000207159 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-11-28 no assertion criteria provided clinical testing

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