rs794729136

chr12-32877909-GCCT-AGGC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001005242.3(PKP2):c.968_971inv(p.Gln323_Ala324delinsArgLeu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. QA323R?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-32877909-GCCT-AGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.968_971inv	p.Gln323_Ala324delinsArgLeu	missense_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.968_971inv	p.Gln323_Ala324delinsArgLeu	missense_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This variant, c.968_971delinsGCCT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the PKP2 protein (p.Gln323_Ala324delinsArgLeu). This variant is present in population databases (rs745882420, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy (PMID: 34120153). ClinVar contains an entry for this variant (Variation ID: 1693192). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 08, 2023

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 08, 2024

This variant changes two consecutive amino acids of the PKP2 protein (p.Gln323Arg and p.Ala324Leu). To our knowledge, functional studies have not been reported for this variant. This variant was identified in 41 individuals from a control group, none of whom had diagnoses related to arrhythmogenic cardiomyopathy (PMID: 34120153). This variant has been identified in 12/281568 chromosomes in the general population by the Genome Aggregation Database (gnomAD) (PMID: 34120153). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2022

Reported in association with cardiomyopathy in published literature (Dries et al., 2021); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34120153) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.968_971delAGGCinsGCCT variant (also known as p.Q323_A324delinsRL), located in coding exon 3 of the PKP2 gene, results from an in-frame deletion of AGGC and insertion of GCCT at nucleotide positions 968 to 971. This results in the substitution of glutamine and alanine residues for arginine and leucine residues at codons 323 and 324. This variant has been reported in non-arrhythmogenic cardiomyopathy control individuals from a PKP2 study cohort (Dries AM et al. Genet Med, 2021 Oct;23:1961-1968). These amino acid positions are not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794729136; hg19: chr12-33030843;