ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.397C>T (p.Gln133Ter) (rs794729132)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183801 SCV000236282 pathogenic not provided 2011-11-30 criteria provided, single submitter clinical testing This mutation is denoted Gln133Stop (aka Q133X) at the protein level and c.397 C>T at the cDNA level. The Gln133Stop mutation in the PKP2 gene has been reported multiple times in association with ARVC (Van Tintelen et al, 2006; Cox et al, 2011; Kapplinger et al, 2011). Van Tintelen et al. (2006) initially identified the Gln133Stop mutation in two individuals diagnosed with ARVC, and this mutation was absent from 300 control alleles (Van Tintelen et al, 2006). Haplotype analysis in these two individuals revealed shared alleles, suggesting the Gln133Stop mutation may be a founder mutation in the Dutch population (Van Tintelen et al, 2006). Cox et al. (2011) identified the Gln133Stop mutation in seven additional probands with ARVC, three of whom harbored a missense variant of unknown significance in the DSG2 gene (Cox et al, 2011). The Gln133Stop mutation is predicted to cause a loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in ARVC panel(s).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000624999 SCV000743460 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2014-10-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193344 SCV001362098 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2019-11-04 criteria provided, single submitter clinical testing Variant summary: PKP2 c.397C>T (p.Gln133X) 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 250340 control chromosomes (gnomAD). c.397C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and has been shown to cosegregate with disease in families (e.g. Groeneweg_2015, vanTintelen_2006). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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