rs878898365

Positions:

• chr12-32868959-C-A
• chr12-32868959-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.1138G>T​(p.Glu380Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,322 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.08

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32868959-C-A is Pathogenic according to our data. Variant chr12-32868959-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32868959-C-A is described in Lovd as [Pathogenic]. Variant chr12-32868959-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1138G>T	p.Glu380Ter	stop_gained	4/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1138G>T	p.Glu380Ter	stop_gained	4/13	1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461322 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726994

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 03, 2023

This variant changes 1 nucleotide in exon 4 in the armadillo repeat 1 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and sudden cardiac arrest (PMID: 28472724). 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 cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 16, 2023

This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with arrhythmogenic cardiomyopathy or history of sudden cardiac arrest (PMID 28472724, 31402444). It has also been identified in population genetic studies (33968641, 28471438). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

PKP2: PVS1, PM2, PS4:Moderate -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

The p.E380* variant (also known as c.1138G>T), located in coding exon 4 of the PKP2 gene, results from a G to T substitution at nucleotide position 1138. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 09, 2017

Variant summary: The PKP2 c.1138G>T (p.Glu380X) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1237C>T, p.Arg413X; c.1613G>A, p.Trp538X; c.1912C>T, p.Gln638X; c.2013delC, p.Lys672fsX12). Mutation taster predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121400 control chromosomes. The variant of interest has not been reported in peer-reviewed publications and/or by clinical diagnostic laboratories. ARVC and LOVD databases report this variant citing a poster material published in a journal (Tsatsopoulou et al. European Heart Journal 2007;28:Suppl; 382) in one proband with TCF positive ARVC who had positive family history of disease with five affected relatives. Both databases have classified it as pathogenic. Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		4.1

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: rs878898365; hg19: chr12-33021893;