ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1444A>G (p.Thr482Ala) (rs397516999)

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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 RCV000038171 SCV000061837 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766572 SCV000236227 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing The T526A variant in the PKP2 gene has been reported previously in a family with ARVC; however, it did notco-segregate with the disease phenotype (Ostrowska et al., 2012). Cerrone et al (2014) identified T526A in a patientwith Brugada syndrome and performed in vitro analyses which demonstrated that T526A is associated with a sodiumcurrent deficit. However, it is currently unclear whether variants in desmosomal proteins directly contribute todeveloping Brugada syndrome and/or act as phenotypic modifiers (Cerrone et al., 2014; Campuzano et al., 2016).The T526A variant was not observed in approximately 6,500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the ExomeAggregation Consortium (ExAC). Although the T526A variant is a non-conservative amino acid substitution, thissubstitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likelydoes not alter the protein structure/function. A variant in the same residue (T526M) has been published in associationwith ARVC (Stenson et al., 2014); however, T526M has also been reported in 0.6-0.9% of alleles from individuals ofAfrican/African American ancestry and in 0.2% of alleles from individuals of European ancestry, indicating it may be arare benign variant in these populations (NHLBI ESP, ExAC, 1000 Genomes Project).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000038171 SCV000740394 likely benign not specified 2017-04-28 criteria provided, single submitter clinical testing
Invitae RCV000640013 SCV000761600 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 526 of the PKP2 protein (p.Thr526Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs397516999, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in two individuals affected with a PKP2-related disease (PMID: 24352520, 28341588). ClinVar contains an entry for this variant (Variation ID: 45032). Experimental studies have shown that this missense change cannot rescue the sodium current deficit observed in PKP2-KD cells (PMID: 24352520). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000640013 SCV001138681 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000640013 SCV001269795 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color RCV001182019 SCV001347333 uncertain significance Cardiomyopathy 2020-04-29 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157413 SCV000207153 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-08-14 no assertion criteria provided clinical testing

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