ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.369G>A (p.Trp123Ter)

dbSNP: rs774663443
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183724 SCV000236202 pathogenic not provided 2021-11-30 criteria provided, single submitter clinical testing Reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) and inherited cardiomyopathy in the published literature (van Lint et al., 2019; Marschall et al., 2019; Kolokotronis et al., 2020); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense 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; Reported in ClinVar (ClinVar Variant ID#201970; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31386562, 31737537, 32659924, 34816084, 32615795)
Ambry Genetics RCV000621084 SCV000734938 pathogenic Cardiovascular phenotype 2024-05-07 criteria provided, single submitter clinical testing The p.W123* pathogenic mutation (also known as c.369G>A), located in coding exon 3 of the PKP2 gene, results from a G to A substitution at nucleotide position 369. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. A different nucleotide change resulting in the same protein impact (c.368G>A, p.W123*) has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and affected family members (Aneq MÅ et al. Scand. Cardiovasc. J., 2012 Apr;46:72-5; Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001068398 SCV001233510 pathogenic Arrhythmogenic right ventricular dysplasia 9 2023-11-08 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. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs774663443, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 22035158, 28600387). ClinVar contains an entry for this variant (Variation ID: 201970). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000183724 SCV001250085 pathogenic not provided 2023-07-01 criteria provided, single submitter clinical testing PKP2: PVS1, PM2, PS4:Moderate, PP4
Revvity Omics, Revvity RCV001068398 SCV002018838 pathogenic Arrhythmogenic right ventricular dysplasia 9 2019-10-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001068398 SCV002811581 pathogenic Arrhythmogenic right ventricular dysplasia 9 2021-11-12 criteria provided, single submitter clinical testing

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