NM_001005242.3(PKP2):c.1896G>A (p.Trp632Ter) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 12, 2022
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:: RCV000656557.5

Allele description [Variation Report for NM_001005242.3(PKP2):c.1896G>A (p.Trp632Ter)]

NM_001005242.3(PKP2):c.1896G>A (p.Trp632Ter)

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.1896G>A (p.Trp632Ter)

HGVS:

NC_000012.12:g.32821473C>T
NG_009000.1:g.80374G>A
NM_001005242.3:c.1896G>AMANE SELECT
NM_004572.4:c.2028G>A
NP_001005242.2:p.Trp632Ter
NP_004563.2:p.Trp676Ter
NP_004563.2:p.Trp676Ter
LRG_398t1:c.2028G>A
LRG_398:g.80374G>A
LRG_398p1:p.Trp676Ter
NC_000012.11:g.32974407C>T
NM_004572.3:c.2028G>A
p.Trp676X

Protein change:

W632*

Links:

dbSNP: rs193922673

NCBI 1000 Genomes Browser:

rs193922673

Molecular consequence:

NM_001005242.3:c.1896G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.2028G>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
SCV000778599	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001586249	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 12, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16567567, 31386562, 15489853, 23911551, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000778599

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 23, 2018)

unknown

research

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

SCV001586249

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 12, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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
not provided	unknown	unknown	1	not provided	not provided	1	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.

van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, van der Smagt J, Boven LG, Mannens MM, van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, van Gelder IC, Hauer RN.

Circulation. 2006 Apr 4;113(13):1650-8. Epub 2006 Mar 27.

PubMed [citation]

PMID:: 16567567

See all PubMed Citations (6)

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha, SCV000778599.1

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

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

From Invitae, SCV001586249.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 36682). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16567567, 31386562). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp676*) 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).

#	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: Feb 14, 2024

ClinVar

Relating variation to medicine