ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.68G>A (p.Gly23Glu) (rs746530389)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000435317 SCV000536359 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing The G23E variant has not been published as pathogenic or been reported as benign to our knowledge. The G23E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and glutamic acid (E) is wild type in several species. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, data from control individuals were not available to assess whether G23E may be a common benign variant in the general population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000620016 SCV000737820 uncertain significance Cardiovascular phenotype 2016-11-30 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000640009 SCV000761596 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-05-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 23 of the PKP2 protein (p.Gly23Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 393010). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000780606 SCV000918021 uncertain significance not specified 2017-11-01 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.68G>A (p.Gly23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/159624 control chromosomes at a frequency of 0.0000125, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). However, this frequency must be considered with caution since this variant did not pass all quality control filters. This variant was reported in one individual in a cohort screened for HCM, DCM, and ARVC, without strong evidence for causality (Walsh_2017). One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more clinical and functional data become available.
Color RCV001187366 SCV001354140 uncertain significance Cardiomyopathy 2020-02-03 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254745 SCV001430832 uncertain significance Sudden cardiac death 2019-06-26 no assertion criteria provided research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.