rs727504432

Positions:

• chr12-32792711-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.2377del​(p.Ser793ValfsTer94) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.72

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0545 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32792711-CT-C is Pathogenic according to our data. Variant chr12-32792711-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32792711-CT-C is described in Lovd as [Likely_pathogenic]. Variant chr12-32792711-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.2377del	p.Ser793ValfsTer94	frameshift_variant	12/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2377del	p.Ser793ValfsTer94	frameshift_variant	12/13	1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2017	The p.Ser837fs variant in PKP2 has been reported in >10 individuals with clinica l features of ARVC (Gerull 2004, Dalal 2006, Dalal 2006, Dalal 2009, Xu 2010, An toniades 2006, Fressart 2009, Barahona-Dussault 2010, Den Haan 2009, Watkins 200 9, Tan, 2010, Cox 2011, Baskin 2013) and was absent from large population studie s. It has also been reported by other clinical laboratories in ClinVar (Variatio n ID 177995). This variant causes a frameshift, which is predicted to replace th e last 45 amino acid residues of the protein with 93 aberrant residues. This alt eration is predicted to lead to an elongated protein with a termination codon th at is 94 amino acids downstream of the frameshift. In summary, although addition al functional studies are required to fully establish its clinical significance, the p.Ser837fs variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS 4_M, PM4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in multiple families (PMID: 16893920, 17010805). This variant has been reported in over 10 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727 ). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change results in a frameshift in the PKP2 gene (p.Ser837Valfs*94). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PKP2 protein and extend the protein by 48 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 16893920, 17010805, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177995). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Mar 08, 2024	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 17, 2022	This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. This variant has been reported in over 10 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727) and has been shown to segregate with disease in multiple families (PMID: 16893920, 17010805). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 93 different amino acids, and other frameshift and missense variants within the residues lost have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 23812740, 15489853, 19863551, 29997227, 29606362, 17010805, 24585727, 23871674, 21606396, 19880068, 18382419, 19358943, 20857253, 20031617, 16893920, 27532257, 30790397, 30764827, 31447099, 32372669, 31402444, 32522011, 25825460, 31386562, 34120153, 35819174, 36139162, 31319917, 16549640, 20400443, VouliotisA2015[CaseReport], 19279339, 20152563) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.2509delA pathogenic mutation, located in coding exon 13 of the PKP2 gene, results from a deletion of one nucleotide at position 2509, causing a translational frameshift with a predicted alternate stop codon (p.S837Vfs*94). This alteration occurs at the 3' terminus of thePKP2 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 48 amino acids. This frameshift impacts the last 45amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been reported in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat Genet. 2004;36(11):1162-4; Dalal D et al. Circulation. 2006;113(13):1641-9; Dalal D et al. J Am Coll Cardiol. 2006;48(7):1416-24; Watkins DA et al. Heart Rhythm. 2009;6(11 Suppl):S10-7; Fressart V et al. Europace. 2010;12(6):861-8; Cox MG et al. Circulation. 2011;123(23):2690-700; Baskin B et al. Hum Genet. 2013;132(11):1245-52; Philips B et al. Circ Arrhythm Electrophysiol. 2014;7(2):230-6; Hermida A. Eur. J. Heart Fail. 2019;21(6):792-800). This variant was also reported to co-segregate with disease in a few small families with ARVC (Antoniades L et al. Eur Heart J. 2006;27(18):2208-16; Vouliotis A et al. Hosp Chron. 2015;10(3):166-173; Xu T. J. Am. Coll. Cardiol. 2010;55(6):587-97). This variant was also detected in an eight year old proband with hypertrophic cardiomyopathy and her unaffected father (Haggerty CM. Circ Genom Precis Med. 2018 Jul;11(7):e002237). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ventricular tachycardia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 15, 2018

- -

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

Nov 14, 2022

Variant summary: PKP2 c.2509delA (p.Ser837ValfsX94) causes a frameshift which results in an extension of the protein. The variant was absent in 251916 control chromosomes. c.2509delA has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Gerull_2004, Dalal_2006, den Haan_2009, Dalal_2006, Antoniades_2006, Asimaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504432; hg19: chr12-32945645;