rs1353074803

Positions:

• chr12-32792666-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001005242.3(PKP2):​c.2422del​(p.Glu808AsnfsTer79) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.16

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 Likely_pathogenic. Variant got 6 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 0.0366 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32792666-TC-T is Pathogenic according to our data. Variant chr12-32792666-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 464426.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-32792666-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2422del	p.Glu808AsnfsTer79	frameshift_variant	12/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2422del	p.Glu808AsnfsTer79	frameshift_variant	12/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 464426). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 19427443, 24125834; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Glu852Asnfs*79) in the PKP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PKP2 protein. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jul 31, 2017

Testing for our patient was performed at the Invitae laboratory and may overlap with any case data. Given the type of variant, the rarity, and the case data, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is notable that the variant has only reported in Chinese individuals. The variant has been seen in at least 4, possibly 5, unrelated cases of ARVC (not including this patient's family). Qiu et al (2009) observed the variant in 3 of 18 unrelated Chinese patients with ARVC who undwerwent sequencing of just PKP2. THey did not report haplotype or other analyses to determine if these individuals had a common ancestor. Subjects were enrolled in a Chinese national ARVC registry. Bao et al (2013) observed this variant in their Chinese cohort as well, with no details available about how the cohort was recruited (hard to ascertain any overlap with Qiu et al). Multiple ARVC genes were sequenced. It is unclear how many patients the variant was seen in. Invitae notes they have also seen this variant in ARVC cases. Baskin et al (2013) observed the variant in 1 of 195 individuals in a Canadian cohort with suspected ARVC. Ancestry was not reported. The lab report also indicates that the variant has been seen in other individuals with ARVC at Invitae, but when I called to follow up on that, they said our patient was the patient that they were referring to. It is not listed in ClinVar. It is not listed in http://www.arvcdatabase.info/. There is another truncating variant at the neighboring amino acid, listed as likely pathogenic by LMM. In their ClinVar entry for that variant they speak to the possible protein effect: "Heterozygous loss of PKP2 function is an established disease mechanism for ARVC; however it is unclear how the p.Thr851fsExtX50 variant would impact the protein function. Of note, 4 other variants having a similar impact to the protein (p.Ser837fsExtX50, p.Leu847fsExtX50, p.Glu852fsExtX50, p.Lys859fsExtX50) have been described in >15 individuals with ARVC (Gerull 2004, Antoniades 2006, Dalal 2006, Asimaki 2009, Dalal 2009, Fressart 2010, Den Haan 2009, Watkins 2009, Qiu 2009, Xu 2010, Barahona-Dussault 2010, Tan, 2010, Cox 2011, Baskin 2013, Alcalde 2014), suggesting that PKP2 protein extension variants are disease-causing." The lab report notes "while this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the PKP2 protein." The variant was reported online in 1 of 123108 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 8624 individuals of East Asian descent (MAF=0.0058%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

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: rs1353074803; hg19: chr12-32945600;