rs121434421

chr12-32802499-G-Achr12-32802499-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001005242.3(PKP2):c.2071C>T(p.Arg691Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.15

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-32802499-G-A is Pathogenic according to our data. Variant chr12-32802499-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32802499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2071C>T	p.Arg691Ter	stop_gained	10/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2071C>T	p.Arg691Ter	stop_gained	10/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251356 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727052

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 26, 2018	The p.Arg735X variant in PKP2 has been reported in 7 individuals with clinical f eatures of ARVC and segregated with disease in 3 affected relatives (Gerull 2004 , Bao 2013, Alcalde 2014, LMM data). This variant has been identified in 1/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs121434421) and has been reported in ClinVar (Vari ation ID 6755). This nonsense variant leads to a premature termination codon at position 735, which is predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. Transgenic mice expressing p.Arg735X mutant protein in cardiac tissue res ulted in exercise-dependent ARVC phenotype (Cruz 2015). In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner based. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1; PS3_Supp orting. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 09, 2023	The c.2203C>T (p.Arg735*) variant in exon 11 of PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been reported in several unrelated individuals (>15) with arrhythmogenic cardiomyopathy (PMID:32389048, 32268277, 30385303, 28471438, 31319917, 29178656, 24125834, 15489853), also found to be segregated in a family with four affected individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID:24967631). Functional studies on transgenic mice showed that cardiac overexpression of human p.Arg735* in mice induced exercise dependent ARVC phenotype, and thus the pathogenic mechanism of this variant was concluded as dominant negative (PMID: 25857910). This variant was found to be rare (1/251356; 0.000003978) in the general population database gnomAD and classified as pathogenic by several ClinVar submitters (ClinVar ID: 6755). Loss of function variants are known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC/D (PMID: 26743238, 15489853, 17010805, 20031616, 20031617) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 640578, 202005, 6757). Therefore, the c.2203C>T (p.Arg735*) variant in the PKP2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 26, 2019	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change creates a premature translational stop signal (p.Arg735*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs121434421, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with arrythmogenic ventricular cardiomyopathy (ARVC) (PMID: 15489853, 24125834, 24967631). ClinVar contains an entry for this variant (Variation ID: 6755). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Functional studies show that over-expression of human p.(R735*) in mice induced an exercise-dependent ARVC phenotype (Cruz et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32466575, 24125834, 25525159, 17363426, 18382419, 24832006, 24967631, 28008009, 30385303, 28471438, 29178656, 29606362, 30790397, 31737537, 32268277, 32372669, 31386562, 31402444, 33232181, 15489853, 25857910) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PKP2: PVS1, PM2, PS4:Moderate, PS3:Supporting -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

The p.R735* pathogenic mutation (also known as c.2203C>T), located in coding exon 11 of the PKP2 gene, results from a C to T substitution at nucleotide position 2203. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat. Genet., 2004 Nov;36:1162-4; Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Alcalde M et al. PLoS ONE, 2014 Jun;9:e100560; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). Transgenic mice with cardiac-specific expression of this variant developed exercise-dependent right ventricular dysfunction resembling ARVC (Cruz FM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1438-50). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121434421; hg19: chr12-32955433;