ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2062T>C (p.Ser688Pro) (rs144601090)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618784 SCV000737842 uncertain significance Cardiovascular phenotype 2016-12-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000038195 SCV000264145 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-11-24 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000038195 SCV000190465 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000468300 SCV000744697 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000766576 SCV000236246 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing The S688P variant of uncertain significance in the PKP2 gene has previously been reported in association with ARVC (van Tintelen et al., 2006; Cox et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Zhang et al., 2012); however, specific clinical information or segregation data was not provided. This variant has also been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx. This variant is observed in 11/24,028 alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The S688P 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. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000468300 SCV000545229 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 688 of the PKP2 protein (p.Ser688Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs144601090, ExAC 0.03%). This variant has been reported in multiple unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16567567, 20031616, 21606390, 22019812, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 45055). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154180 SCV000061862 uncertain significance not specified 2015-05-16 criteria provided, single submitter clinical testing The p.Ser688Pro variant in PKP2 has been reported in 3 individuals with ARVC (va n Tintelen 2006, Quarta 2011, and Zhang 2011) and identified by our laboratory i n 1 African American child with clinical features of DCM and ARVC and 1 child of mixed ancestry with ARVC. This variant has also been identified in 3/10406 Afri can chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs144601090). Computational prediction tools and conservation a nalysis suggest that the p.Ser688Pro variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, th e clinical significance of the p.Ser688Pro variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000038195 SCV000747967 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-06-28 criteria provided, single submitter clinical testing

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