ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.184C>A (p.Gln62Lys) (rs199601548)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148732 SCV000190467 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000232789 SCV000744717 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000232789 SCV000733172 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing
GeneDx RCV000183769 SCV000236250 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing The Q62K variant of uncertain significance in the PKP2 gene has been reported in multiple individuals with ARVC (van Tintelen et al., 2006; Lahtinen et al., 2008; Fidler et al., 2009; Bauce et al., 2010; Christensen et al., 2010; Xu et al., 2010; Rigato et al., 2013; Zorzi et al., 2015). Initially, van Tintelen et al. (2006) reported Q62K in one individual diagnosed with ARVC who also harbored a canonical splice site variant in PKP2; however, segregation data was not provided. Lahtinen et al. (2008) described an individual with ARVC who was compound heterozygous for Q62K and another variant in PKP2. While Q62K was identified independently in three adult relatives, only one relative fulfilled modified ARVC diagnostic criteria (Lahtinen et al., 2008). In another study, Q62K was observed in two siblings and a parent diagnosed with ARVC (Bauce et al., 2010). However, one sibling also harbored a nonsense variant in the PKP2 gene, the other sibling also harbored the PKP2 nonsense variant and a missense variant in the DSP gene, and the father also harbored the DSP variant (Bauce et al., 2010). Additionally, Christensen et al. (2010) reported Q62K in two unrelated individuals with ARVC; however, an affected sibling of one proband did not harbor Q62K.The Q62K variant has also been reported in at least three individuals without ARVC; one individual diagnosed with end-stage dilated cardiomyopathy (DCM) (Garcia-Pavia et al., 2011), a second individual with a clinical diagnosis of Brugada syndrome (Cerrone et al., 2014), and a third individual with sudden death who was diagnosed with hypertrophic cardiomyopathy (HCM) on autopsy (Sanchez et al., 2016), although this last individual was also found to harbor additional cardiogenetic variants. Q62K has been reported in multiple unrelated individuals referred for cardiac genetic testing at GeneDx, though most individuals were also found to carry additional cardiogenetic variants. Q62K has also been identified in 12/28,465 (0.02%) individuals in the FINRISK and Health 2000 population cohorts; one of whom had a history of arrhythmia and two of whom had a history of heart failure (Lahtinen et al., 2013). In addition, Q62K was observed in 0.03% (34/111,412) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016) and in 0.02% (12/56,930) of alleles from individuals of Finnish ancestry (Lahtinen et al., 2013). Functional studies in human A341 and modified A341D cell lines demonstrated that while Q62K mutant plakophilin 2 protein can properly localize to cell-cell contact sites, it is less stable than wild-type plakophilin 2 and it is unable to recruit desmoplakin to these sites to initiate desmosome assembly (Hall et al., 2009). Further functional studies by Cerrone et al. (2014) using plakophilin 2-depleted human cardiomyocytes found that transient transfection of Q62K mutant plakophilin 2 alone, or together with wild-type plakophilin 2, caused a reduced sodium current which could only be rescued by expressing wild-type plakophilin 2 alone. The Q62K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000232789 SCV000743464 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-07-19 criteria provided, single submitter clinical testing
Invitae RCV000232789 SCV000288601 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-12-07 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000232789 SCV000803625 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 9, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting . PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:19533476).

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