ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1468C>T (p.Arg490Trp) (rs149930872)

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Total submissions: 15
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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 RCV000172581 SCV000051415 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155807 SCV000205518 likely benign not specified 2013-11-04 criteria provided, single submitter clinical testing Arg490Trp in exon 6 of PKP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , orangutan, rhesus macaque, baboon, and marmoset have a tryptophan (Trp) at thi s position despite high nearby amino acid conservation. Addtionally, functional studies have shown that this variant does not impact splicing (Gandjbankhch 201 1). It has also been identified in 0.15% (7/4402) of African American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs149930872). Arg490Trp in exon 6 of PKP2 (rs149930872; allele frequency = 0 .15%, 7/4402) **
PreventionGenetics,PreventionGenetics RCV000155807 SCV000310491 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000155807 SCV000514128 likely benign not specified 2016-10-12 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 RCV000172581 SCV000638865 likely benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577994 SCV000679904 uncertain significance Becker muscular dystrophy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578052 SCV000679905 uncertain significance Dilated cardiomyopathy 3B 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577936 SCV000679906 uncertain significance Duchenne muscular dystrophy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000528781 SCV000679907 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578088 SCV000679908 uncertain significance Brugada syndrome 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577930 SCV000679909 uncertain significance Primary dilated cardiomyopathy 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619186 SCV000737479 likely benign Cardiovascular phenotype 2018-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000771870 SCV000904593 likely benign Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000155807 SCV000920007 likely benign not specified 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.1468C>T (p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing, which was confirmed by Gandjbakhch_2011 using transcriptional analysis in heart tissue. This variant does not affect the expression levels of PKP2 (Gandjbakhch_2011).This variant was found in 112/239690 control chromosomes in gnomAD, predominantly observed in the African subpopulation at a frequency of 0.00095 (22/23170). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Three siblings were found to carry this variant: two were affected/possibly affected and one was unaffected, suggesting this variant is not fully penetrant or does not segregate with disease. Moreover, another variant (DSP p.Glu2343Lys) was found in all three family members and may explain the phenotype in these patients (Gandjbakhch_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000771870 SCV000995384 likely benign Cardiomyopathy 2018-10-02 criteria provided, single submitter clinical testing

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