ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1093A>G (p.Met365Val) (rs143900944)

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Total submissions: 8
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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 RCV000172090 SCV000051039 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151659 SCV000199929 likely benign not specified 2016-03-21 criteria provided, single submitter clinical testing Met365Val in exon 4 of PKP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals (mouse, rat, horse, and elephant) have a valine (Val) at this position despite high nearby amino acid conservation. In addition, computationa l analyses do not suggest a high likelihood of impact to the protein. This varia nt has also been identified in 0.1% (20/16512) of South Asian chromosomes, inclu ding one homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broa; dbSNP rs143900944). Additionally, this variant has been reported in one individual with Brugada snydrome, and in vitro functional studies sugges t this variant may impact protein function (Cerrone 2014); however, these types of assays may not accurately represent biological function. However, the lack of conservation and the frequency in controls suggests that it is likely to be ben ign.
GeneDx RCV000151659 SCV000236182 likely benign not specified 2017-04-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000457033 SCV000557315 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000777990 SCV000914096 likely benign Cardiomyopathy 2018-08-13 criteria provided, single submitter clinical testing
Mendelics RCV000457033 SCV001138682 benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000151659 SCV001338302 likely benign not specified 2020-02-13 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1093A>G (p.Met365Val) 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 0.00027 in 251320 control chromosomes, predominantly at a frequency of 0.0012 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1093A>G has been reported in the literature in at-least one individual who showed a type I ECG after induction flecanide test (Cerrone_2014). However, subsequent reports have not supported a disease causing outcome for this variant (example, Ghouse_2017, Haggerty_2017, Chen_2018, and Campuzano_2019). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. At-least one co-occurrence with another likely pathogenic variant has been observed at our laboratory (SCN5A c.1890G>A, p.Thr630Thr). As pathogenic variants in SCN5A represent the major contribution of Brugada syndrome, this co-occurrence provides additional supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity in a measurement of peak sodium current in cells co-expressing WT and variant constructs. However, these results have not been independently corroborated by subsequent studies. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign(n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000457033 SCV000733166 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing

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