Submissions for variant NM_001005242.3(PKP2):c.2483C>T (p.Thr828Ile)

gnomAD frequency: 0.00002  dbSNP: rs370599966

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127445	SCV000171010	benign	not specified	2012-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171153	SCV001333837	uncertain significance	Cardiomyopathy	2017-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171153	SCV001346476	uncertain significance	Cardiomyopathy	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 872 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few Dutch families affected with arrhythmogenic cardiomyopathy (PMID: 16567567, 25820315, 34317382). This variant was observed in cis with an upstream pathogenic truncating variant (c.397C>T, p.Gln133X) in all the carriers, suggesting that this variant may not have been the cause of arrhythmogenic cardiomyopathy in these families. This variant has been identified in 3/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127445	SCV001362099	likely benign	not specified	2019-11-04	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.2615C>T (p.Thr872Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251468 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2615C>T has been reported in the literature in multiple individuals affected with Arrhythmia co-occurring with pathogenic variant PKP2 c.397C>T (p.Q133*) (e.g. Groeneweg_2015, van Tintelen_2006). This suggests the variant of interest may be in linkage with the pathogenic variant c.397C>T and provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV001224075	SCV001396253	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 872 of the PKP2 protein (p.Thr872Ile). This variant is present in population databases (rs370599966, gnomAD 0.002%). This missense change has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 21636032). ClinVar contains an entry for this variant (Variation ID: 138691). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.