ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1418A>G (p.Asn473Ser) (rs144536197)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172580 SCV000051037 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038168 SCV000061834 likely benign not specified 2014-10-08 criteria provided, single submitter clinical testing p.Asn517Ser in exon7 of PKP2: This variant has been reported in 1 Caucasian indi vidual with sudden cardiac death (Ip 2013). While this variant is rare in the ge neral population (3/8600 European American chromosomes by the NHLBI Exome Sequen cing Project,; rs144536197), it appears to be common in Ashkenazi Jewish individuals (3/90 chromosomes, 3.3%; LMM unpublished data). In addition, asparagine (Asp) at position 517 is not conserved in mammals or evolutionarily distant species, supporting that a change at this position ma y be tolerated. In summary, the frequency of this variant in the Ashkenazi Jewis h population indicates it is likely benign, although a modifying effect cannot b e ruled out.
GeneDx RCV000172580 SCV000236288 likely benign not provided 2020-07-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23861362, 23962865, 27153395, 28301460)
Ambry Genetics RCV000251493 SCV000318012 benign Cardiovascular phenotype 2018-01-16 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
Invitae RCV001086816 SCV000638866 likely benign Arrhythmogenic right ventricular dysplasia 9 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771855 SCV000904574 benign Cardiomyopathy 2018-07-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038168 SCV000920005 likely benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1550A>G (p.Asn517Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 276874 control chromosomes, predominantly within the Ashkenazi Jewish subpopulation at a frequency of 0.011 in the gnomAD database, including 1 homozygote. This frequency within Ashkenazi Jewish control individuals is approximately 10 fold above the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1550A>G has been reported in the literature in individuals affected with cardiomyopathy and cancer. However, these reports do not provide unequivocal conclusions about an association of the variant with cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001086816 SCV001269796 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2019-08-02 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000771855 SCV001332772 benign Cardiomyopathy 2018-10-16 criteria provided, single submitter clinical testing
Clinical Genetics,Academic Medical Center RCV000172580 SCV001918063 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000172580 SCV001931322 likely benign not provided no assertion criteria provided clinical testing

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