rs193922672

chr12-32841103-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.1481G>A(p.Trp494Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,460,862 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: 0.0000027 (0 hom.)
• Consequence: PKP2 NM_001005242.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 3.58

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 12-32841103-C-T is Pathogenic according to our data. Variant chr12-32841103-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32841103-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1481G>A	p.Trp494Ter	stop_gained	6/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1481G>A	p.Trp494Ter	stop_gained	6/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251382 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000153

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: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Oct 31, 2019	The c.1613G>A (p.Trp538Ter) variant is a single nucleotide substitution in the coding exon 7 (14 exons in total) of the PKP2 gene. This variant substitutes a tyrosine residue to a premature termination codon at amino acid position 538 (882 in total) and is predicted to result in nonsense-mediated mRNA decay (NMD). This variant was observed in the exome Genome Aggregation Database (gnomAD) with an overall allele frequency of 4/251382 (no homozygotes), indicating it is not a common benign variant in the populations represented in these databases. To the best of our knowledge, this variant has been reported several times in the literature with individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy 9, including some individuals with early onset symptoms (PMID: 16549640, 17010805, and 20031617). Age and gender have been reported to have influences on penetrance of this disease. In ClinVar, this variant has been classified as Pathogenic by multiple clinical laboratories. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Feb 25, 2022	The c.1613G>A (p.Trp538*) nonsense variant in the PKP2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 16549640, 19863551, 20031617, 20152563, 20857253, 21606390, 26743238, 32268277]. ClinVar contains an entry for this variant (Variation ID: 36680). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 20, 2021	The c.1613G>A (p.Trp538Ter) variant identified in PKP2 gene is a nonsense variant that leads to the premature termination of the protein at amino acid 538/882 (exon 7/14; NM_004572.3). This variant is also called c.1481G>A, (p.Trp494Ter) annotated from transcript NM_001005242.3. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. It is reported in ClinVar as Pathogenic (VarID:36680) and has been reported in many affected individuals in the literature [PMID:26743238, 24585727, 21606390, others]. Given its deleterious nature, absence in population databases, and presence in many affected individuals in the literature, the c.1613G>A (p.Trp538Ter) variant identified in PKP2 gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change creates a premature translational stop signal (p.Trp538*) 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 (rs193922672, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16549640, 19863551, 20031617, 20152563, 26743238). ClinVar contains an entry for this variant (Variation ID: 36680). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 10, 2017	The c.1613G>A (p.Trp538*) nonsense variant in the PKP2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 16549640, 19863551, 20031617, 20152563, 20857253, 21606390, 26743238]. This variant in the PKP2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 12, 2021	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This variant changes 1 nucleotide in exon 7 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 19863551, 20031617, 20152563, 26743238). This variant has been identified in 3/246156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2019	The p.Trp538X variant in PKP2 has been reported in >15 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 3 affected relatives from 2 families (Dalal 2006, Den Haan 2009, Barahona Dussault 2009, Xu 2010, Tan 2010, Quarta 2011, Baskin 2013, Philips 2014, Adler 2016, LMM data). It was also identified in 1 child that died unexpectedly who also carried a pathogenic variant in CACNA1C (Dewar 2017) and has also been reported by other clinical laboratories in ClinVar (Variation ID 36680). Additionally, this variant was identified in 2 asymptomatic individuals (Perrin 2013) and in 0.03% (3/10078) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 538, which is predicted to lead to a truncated or absent protein. Loss of function of the PKP2 gene is strongly associated to autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 31, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 17010805, 23812740, 16549640, 34120153, 19358943, 23810883, 25525159, 20152563, 20031617, 24585727, 19863551, 21606390, 28807990, 29128982, 26743238, 30765282, 32268277, 32372669, 31386562, 31402444, 30354609, 20857253, 34469894, 31447099) -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 08, 2021	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 18, 2023

This variant changes 1 nucleotide in exon 7 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 over ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 19863551, 20031617, 20152563, 26743238). This variant has been identified in 3/246156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The p.W538* pathogenic mutation (also known as c.1613G>A), located in coding exon 7 of the PKP2 gene, results from a G to A substitution at nucleotide position 1613. This changes the amino acid from a tryptophan to a stop codon within coding exon 7. This alteration has been previously described in several individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Dalal D et al. J Am Coll Cardiol. 2006;48:1416-24; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35; Baskin B et al. Hum. Genet., 2013 Nov;132:1245-52; Rabey I et al. Circulation, 2018 Aug;138:642-645). 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. -

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

Feb 01, 2021

Variant summary: PKP2 c.1613G>A (p.Trp538X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 1.6e-05 in 251782 control chromosomes (gnomAD and publication data). c.1613G>A has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Dalal_2006, Den Haan_2009, Barahona-Dussault_2010). 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. Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		5.2

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: rs193922672; hg19: chr12-32994037;