NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter) AND Arrhythmogenic right ventricular dysplasia 9

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 7, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000463730.13

Allele description

NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter)

Other names:

p.L92*:TTG>TAG

HGVS:

NC_000012.12:g.32878981A>T
NG_009000.1:g.22866T>A
NM_001005242.3:c.275T>AMANE SELECT
NM_004572.4:c.275T>A
NP_001005242.2:p.Leu92Ter
NP_004563.2:p.Leu92Ter
NP_004563.2:p.Leu92Ter
LRG_398t1:c.275T>A
LRG_398:g.22866T>A
LRG_398p1:p.Leu92Ter
NC_000012.11:g.33031915A>T
NM_004572.3:c.275T>A

Protein change:

L92*

Links:

dbSNP: rs763639737

NCBI 1000 Genomes Browser:

rs763639737

Molecular consequence:

NM_001005242.3:c.275T>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.275T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 9 (ARVD9)
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9; Arrhythmogenic right ventricular cardiomyopathy, type 9; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9
Identifiers:: MONDO: MONDO:0012180; MedGen: C1836906; OMIM: 609040

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545251	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15489853, 20400443, 24832006, 28492532
SCV000840039	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 11, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545251

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 7, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000840039

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 11, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.

Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L.

Nat Genet. 2004 Nov;36(11):1162-4. Epub 2004 Oct 17. Erratum in: Nat Genet. 2005 Jan;37(1):106.

PubMed [citation]

PMID:: 15489853

Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.

Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, et al.

Europace. 2010 Jun;12(6):861-8. doi: 10.1093/europace/euq104. Epub 2010 Apr 16.

PubMed [citation]

PMID:: 20400443

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000545251.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). This particular variant has been reported in the literature in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 24832006). ClinVar contains an entry for this variant (Variation ID: 202026). This sequence change creates a premature translational stop signal at codon 92 (p.Leu92*) of the PKP2 gene. It is expected to result in an absent or disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.275T>A (p.Leu92*) variant in the PKP2 gene has been detected in two patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) from a cohort of 135 patients. [PMID 20400443 ]. This c.275T>A change creates a premature stop codon at amino acid position 92 of the PKP2 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This c.275T>A (p.Leu92*) variant thus classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

ClinVar

Relating variation to medicine