NM_001005242.3(PKP2):c.2352C>T (p.Gly784=) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 30, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000155651.6

Allele description [Variation Report for NM_001005242.3(PKP2):c.2352C>T (p.Gly784=)]

NM_001005242.3(PKP2):c.2352C>T (p.Gly784=)

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.2352C>T (p.Gly784=)

Other names:

p.G828G:GGC>GGT

HGVS:

NC_000012.12:g.32796114G>A
NG_009000.1:g.105733C>T
NM_001005242.3:c.2352C>TMANE SELECT
NM_004572.4:c.2484C>T
NP_001005242.2:p.Gly784=
NP_004563.2:p.Gly828=
NP_004563.2:p.Gly828=
LRG_398t1:c.2484C>T
LRG_398:g.105733C>T
LRG_398p1:p.Gly828=
NC_000012.11:g.32949048G>A
NM_004572.3:c.2484C>T
p.Gly828Gly

Links:

dbSNP: rs727504509

NCBI 1000 Genomes Browser:

rs727504509

Molecular consequence:

NM_001005242.3:c.2352C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_004572.4:c.2484C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000205360	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 30, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23671136, 20031617, 17041889, 19358943, 23354045, 23810883, 20857253, 23810894, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000205360

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 30, 2019)

germline

clinical testing

PubMed (9)
[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	1	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

Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

den Haan AD, Tan BY, Zikusoka MN, Lladó LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP.

Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. doi: 10.1161/CIRCGENETICS.109.858217. Epub 2009 Jun 3.

PubMed [citation]

PMID:: 20031617
PMCID:: PMC2801867

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000205360.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly828Gly variant in PKP2 has been reported as homozygous in 1 adult with ARVC and as heterozygous in her unaffected parents (Awad 2006, Dalal 2009, den Haan 2009, Tan 2010) and as homozygous in 1 asymptomatic teenager with RBBB and other abnormal EKG findings (Perrin 2013). It was also identified in 2/66738 European chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/; dbSNP rs727504509). mRNA studies showed that the 2484C>T variant results in a 7 bp deletion at the end of exon 12, resulting in a frameshift that extends the coding sequence by 145 bp (48 amino acids; Awad 2006, Kim 2013). While it is unclear if this variant would be disease-causing in isolation, the available evidence suggests that it is likely pathogenic when seen in homozygosity or with a second PKP2 variant. However, additional studies are needed to fully assess the clinical significance of this variant.

#	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		1	not provided	1	not provided

Last Updated: Apr 15, 2024

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