ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1872G>T (p.Glu624Asp) (rs370219248)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766574 SCV000236242 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PKP2 gene. The E624D variant has been reported in a female with sudden unexplained death at 33 years of age (Sanchez et al., 2016); however, this individual also harbored additional variants, including a frameshift variant in the TTN gene considered to be disease-causing. This variant has also been observed in two other individuals referred for arrhythmia/cardiomyopathy genetic testing at GeneDx, although these individuals also harbored other variants in different genes and no informative segregation data are available to further clarify the role of this variant in disease. The E624D variant is observed at a global allele frequency of 19/246044 (0.008%) alleles in large population cohorts (Lek et al., 2016). The E624D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000473176 SCV000545221 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-08-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 624 of the PKP2 protein (p.Glu624Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs370219248, ExAC 0.02%). This variant has been observed in an individual with sudden unexplained death who carried additional variants in other genes (PMID: 27930701). ClinVar contains an entry for this variant (Variation ID: 201999). 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 aspartic 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 RCV000183761 SCV000698468 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1872G>T (p.Glu624Asp) 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 7.7e-05 in 246044 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in PKP2 causing Cardiomyopathy (7.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1872G>T has been reported in the literature in an individual affected with undetermined sudden death (Sanchez_2016). This report does not provide an unequivocal conclusion about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (TTN c.30515_17delAAG, p.E10172fs; a Spanish founder mutation in PKP2, c.987del, p.S329RfsX351), providing supporting evidence for a benign role (Sanchez_2016 and an unpublished reference, A. Diez_Juan et al, 2011, However, considering some patients with cardiomyopathies could have complex genotypes in the main desmosomal genes that could develop early and severe phenotypes, the co-occurrence information would not necessarily prove the non-pathogenicity of our variant of interest. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766574 SCV001250084 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000473176 SCV001269281 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-05-01 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 RCV001181144 SCV001346238 uncertain significance Cardiomyopathy 2019-02-10 criteria provided, single submitter clinical testing

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