ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.307C>A (p.Pro103Thr) (rs139215336)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430174 SCV000515737 uncertain significance not specified 2016-07-05 criteria provided, single submitter clinical testing The P103T variant of uncertain significance in the PKP2 gene has been reported previously in one individual with ARVC who also harbors the T358I variant in the DSC2 gene (Rasmussen et al., 2014). Segregation studies in this family showed that the P103T variant in the PKP2 gene is paternally inherited and the T358I variant in the DSC2 gene is maternally inherited from asymptomatic parents (Rasmussen et al., 2014). This variant has also been reported in one individual with a diagnosis of HCM; however, detailed clinical history, family history and segregation data were not provided (Lopes et al., 2015). The P103T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P103T 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. Nevertheless, this substitution occurs at a position that is not conserved across species; Threonine is the wild-type amino acid at this position in the Armadillo. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, functional studies show that the P103T variant results in normal expression of PKP2 (Rasmussen et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000530560 SCV000638897 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 103 of the PKP2 protein (p.Pro103Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs139215336, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with arrhythmogenic cardiomyopathy and in an individual affected with hypertrophic cardiomyopathy (PMID: 24704780, 25351510). ClinVar contains an entry for this variant (Variation ID: 379132). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PKP2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727359 SCV000707849 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620133 SCV000737751 uncertain significance Cardiovascular phenotype 2019-07-22 criteria provided, single submitter clinical testing Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769397 SCV000900789 uncertain significance Cardiomyopathy 2017-06-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000530560 SCV001271395 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-06-19 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 RCV000769397 SCV001354749 uncertain significance Cardiomyopathy 2020-02-12 criteria provided, single submitter clinical testing

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