ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.368G>A (p.Trp123Ter) (rs760576804)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000183716 SCV000229050 pathogenic not provided 2014-09-22 criteria provided, single submitter clinical testing
GeneDx RCV000183716 SCV000236194 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The W123X pathogenic variant in the PKP2 gene has been previously reported in association with ARVC and/or sudden cardiac arrest and has been shown to segregate with disease in one family (Aneq et al., 2012; Mellor et al., 2017). In addition, W123X is classified in ClinVar as pathogenic by another clinical laboratory (SCV000229050.3; Landrum et al., 2016). The W123X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Many other nonsense variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, W123X is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, W123X in the PKP2 gene is interpreted as a pathogenic variant.
Invitae RCV000177212 SCV000638899 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-02-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp123*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with arrhythmias and in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 22035158, 25445213). ClinVar contains an entry for this variant (Variation ID: 196395). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000177212 SCV000840040 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-06-02 criteria provided, single submitter clinical testing The c.368G>A (p.Trp123*) variant in the PKP2 gene has been detected in a family with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 22035158]. The variant segregated within the family; only one carrier individual was clinically asymptomatic. This variant creates a premature stop codon at amino acid position 123 of the PKP2 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant is thus classified as pathogenic.
Color RCV001177380 SCV001341578 pathogenic Cardiomyopathy 2019-05-16 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196694 SCV001367325 pathogenic Congestive heart failure; Complete atrioventricular canal defect 2019-10-04 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP3. This variant was detected in homozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197042 SCV001367677 pathogenic Right ventricular cardiomyopathy; Ventricular tachycardia 2020-03-17 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198539 SCV001369517 pathogenic mitochondrial 2019-07-09 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001177380 SCV001369645 pathogenic Cardiomyopathy 2019-10-10 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. This variant was detected in heterozygous state.

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