rs727504509
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BS2_Supporting
The NM_001005242.3(PKP2):c.2352C>T(p.Gly784Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 synonymous
NM_001005242.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.32
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP5
Variant 12-32796114-G-A is Pathogenic according to our data. Variant chr12-32796114-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178879.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Likely_pathogenic=3}. Variant chr12-32796114-G-A is described in Lovd as [Pathogenic].
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251434Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135896
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461194Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 726958
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GnomAD4 genome 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74322
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 18, 2017 | In a homozygous state, the c.2484C>T variant (rs727504509) has been reported in the medical literature in two individuals with arrhythmogenic right ventricular dysplasia (Awad 2006, Dalal 2009, den Haan 2009, and Tan 2010) as well as an asymptomatic teenager with abnormal EKG findings (Perrin 2013). Individuals who were heterozygous for the variant were unaffected (Awad 2006). Functional evidence indicates that the c.2484C>T variant creates a cryptic splice site that causes a frame shift, which disrupts the last 54 amino acids, adds an additional 48 residues, and alters protein localization and function (Awad 2006 and Kim 2013). The c.2484C>T variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency of 0.0036% in non-Finnish Europeans (identified in 4 out of 111,662 chromosomes) and is listed the ClinVar database with conflicting interpretations of pathogenicity (variant of uncertain significance/likely pathogenic; Variation ID: 178879). Based on the available evidence, the c.2484C>T variant is likely to be pathogenic. Pathogenic variants in PKP2 are typically inherited in an autosomal dominant manner and are associated with arrhythmogenic right ventricular dysplasia 9 (MIM: 609040). Because the c.2484C>T variant is reported to be associated with autosomal recessive arrhythmogenic right ventricular dysplasia, it is unlikely that this variant is responsible for the patient’s phenotype; however, a modifying role cannot be ruled out. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Identified in isolation and in conjunction with additional cardiogenetic variants in individuals in the literature, but segregation data are limited or absent at this time (Ali et al., 2018; Dalal et al., 2009); Identified in at least two patients in the literature with ARVC who were homozygous for c.2484 C>T and heterozygous relatives were reported to be unaffected or asymptomatic (Awad et al., 2006; Tan et al., 2010; den Haan et al., 2009); This variant is associated with the following publications: (PMID: 23810883, 28573431, 17041889, 23354045, 29961461, 20857253, 20031617, 30205876, 19358943, 27030002, 31402444, 32180835, 33206225, 33595719, 35059364, 31963859, 33802229, 34079803, 33536939, 28329361, 23671136, 24352520, 24632794) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | PKP2: PM2:Supporting, PP3 - |
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2023 | 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. Studies have shown that this variant results in partial skipping of exon 12 and introduces a new termination codon (PMID: 17041889). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 178879). This variant has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy or clinical features of this condition in the homozygous state (PMID: 17041889, 23810883, 29961461). This variant is present in population databases (rs727504509, gnomAD 0.004%). This sequence change affects codon 828 of the PKP2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKP2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | The c.2484C>T variant (also known as p.G828G), located in coding exon 12 of the PKP2 gene, results from a C to T substitution at nucleotide position 2484. This nucleotide substitution does not change the glycine at codon 828. This variant has been reported in the homozygous state in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, it has also been reported in an asymptomatic homozygote, as well as in unaffected heterozygotes (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35;Perrin MJ et al. J Am Coll Cardiol, 2013 Nov;62:1772-9; Ali M et al. Indian Heart J 2018 Oct;70:421-426). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies demonstrated splicing impact in the majority of transcripts derived from the variant allele (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; Kim C et al. Nature, 2013 Feb;494:105-10). Based on the supporting evidence, this variant is likely to be pathogenic for arrhythmogenic right ventricular cardiomyopathy (ARVC) when present along with a second pathogenic variant on the other allele; however, its clinical significance in the heterozygous state is unclear. - |
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2024 | Variant summary: PKP2 c.2484C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant creates a cryptic splice site and introduces a premature termination codon (Awad_2006). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes. c.2484C>T has been reported in the literature in the homozygous and compound heterozygous states in individuals affected with Arrhythmogenic Right Ventricular Dysplasia (ARVD)/Cardiomyopathy (Awad_2006, Bhonsale_2013, Janin_2022, Ali_2018) and homozygous in at least one asymptomatic individual with abnormal EEG findings (Perrin_2013). Heterozygous individuals have been reported as unaffected (e.g. Awad_2006, Yang_2022). These data indicate that the variant is likely to be associated with autosomal recessive disease. At least one experimental study using iPSC cardiomyocyte cell lines homozygous for this variant showed that these cells exhibit characteristics of Arrhythmogenic Right Ventricular Dysplasia (e.g. Wen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 29961461, 17041889, 23671136, 35838873, 23810883, 25971409, 36129056). ClinVar contains an entry for this variant (Variation ID: 178879). To our knowledge, this variant has not been reported in patients with autosomal dominant ARVD. Based on the evidence outlined above, this variant is pathogenic for autosomal recessive ARVD. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 30, 2019 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly828Gly variant in PKP2 has been reported as homozygous in 1 adult with ARVC and as heterozygous in her unaffected parents (Awad 2006, Dalal 2009, den Haan 2009, Tan 2010) and as homozygous in 1 asymptomatic teenager with RBBB and other abnormal EKG findings (Perrin 2013). It was also identified in 2/66738 European chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/; dbSNP rs727504509). mRNA studies showed that the 2484C>T variant results in a 7 bp deletion at the end of exon 12, resulting in a frameshift that extends the coding sequence by 145 bp (48 amino acids; Awad 2006, Kim 2013). While it is unclear if this variant would be disease-causing in isolation, the available evidence suggests that it is likely pathogenic when seen in homozygosity or with a second PKP2 variant. However, additional studies are needed to fully assess the clinical significance of this variant. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | This synonymous variant in the PKP2 protein is predicted to impact RNA splicing by creating a new splice donor site 7 nucleotides upstream from the native donor site. A functional RNA study in cells derived from a homozygous individual has shown that this variant causes aberrant splicing and deletion of the last 7 nucleotides in exon 12 (PMID: 17041889). The ensuing frameshift is expected to disrupt the last 54 amino acids of PKP2 protein and extend the C-terminus by 48 amino acids. This variant has been reported in homozygosity in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 17041889, 29961461). One of the proband's three heterozygous, teenaged children were unaffected. This variant has been observed in multiple individuals from the same cohort (PMID: 19358943, 20031617, 20857253, 23671136, 23810883, 23810894) and it is not clear how many unrelated, affected individuals are known to carry this variant. This variant has been identified in 5/282794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with autosomal recessive ARVC, the available evidence is insufficient to determine the role of this variant in autosomal dominant ARVC conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at