NM_001005242.3(PKP2):c.1689dup (p.Val564fs) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 1, 2024
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:: RCV000038187.8

Allele description [Variation Report for NM_001005242.3(PKP2):c.1689dup (p.Val564fs)]

NM_001005242.3(PKP2):c.1689dup (p.Val564fs)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.1689dup (p.Val564fs)

Other names:

p.Val608CysfsX6

HGVS:

NC_000012.12:g.32822617dup
NG_009000.1:g.79230dup
NM_001005242.3:c.1689dupMANE SELECT
NM_004572.4:c.1821dup
NP_001005242.2:p.Val564fs
NP_004563.2:p.Val608fs
NP_004563.2:p.Val608fs
LRG_398t1:c.1821dup
LRG_398:g.79230dup
LRG_398p1:p.Val608fs
NC_000012.11:g.32975551dup
NM_001005242.3:c.1689dupTMANE SELECT
NM_004572.3:c.1821dup
NM_004572.3:c.1821dupT
c.1821_1822insT

Protein change:

V564fs

Links:

dbSNP: rs397517010

NCBI 1000 Genomes Browser:

rs397517010

Molecular consequence:

NM_001005242.3:c.1689dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004572.4:c.1821dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

Recent activity

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probable anion transporter 6, chloroplastic isoform X1 [Cucurbita moschata]
probable anion transporter 6, chloroplastic isoform X1 [Cucurbita moschata]
gi|1279786430|ref|XP_022946154.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061854	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 20, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23671136, 24033266
SCV004812561	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28588093, 31319917, 34469894, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061854

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 20, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004812561

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 1, 2024)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.

Bhonsale A, James CA, Tichnell C, Murray B, Madhavan S, Philips B, Russell SD, Abraham T, Tandri H, Judge DP, Calkins H.

Circ Arrhythm Electrophysiol. 2013 Jun;6(3):569-78. doi: 10.1161/CIRCEP.113.000233. Epub 2013 May 13.

PubMed [citation]

PMID:: 23671136

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061854.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Val608fs variant in PKP2 has been reported in 2 individuals with clinical features of ARVC (Bhonsale 2013, LMM unpublished data). This variant has been id entified in 1/111470 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517010) and has been previ ously reported in ClinVar (Variation ID 45047). This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 608 and leads to a premature termination codon 6 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Val608fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_S (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	1	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812561.1

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

Description

This sequence change in PKP2 is a frameshift variant predicted to cause a premature stop codon, p.(Val564Cysfs*6), in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0009% (10/1,111,944 alleles) in the European (non-Finnish) population. This variant has been reported in at least four unrelated probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy and segregates with disease in at least two families (PMID: 31319917, 28588093, 34469894). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PP1, PS4_Supporting

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

Last Updated: Sep 29, 2024

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