NM_001005242.3(PKP2):c.1760A>G (p.Tyr587Cys) AND Cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 25, 2023
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:: RCV001177374.4

Allele description [Variation Report for NM_001005242.3(PKP2):c.1760A>G (p.Tyr587Cys)]

NM_001005242.3(PKP2):c.1760A>G (p.Tyr587Cys)

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.1760A>G (p.Tyr587Cys)

HGVS:

NC_000012.12:g.32822546T>C
NG_009000.1:g.79301A>G
NM_001005242.3:c.1760A>GMANE SELECT
NM_004572.4:c.1892A>G
NP_001005242.2:p.Tyr587Cys
NP_004563.2:p.Tyr631Cys
NP_004563.2:p.Tyr631Cys
LRG_398t1:c.1892A>G
LRG_398:g.79301A>G
LRG_398p1:p.Tyr631Cys
NC_000012.11:g.32975480T>C
NM_004572.3:c.1892A>G

Protein change:

Y587C

Links:

dbSNP: rs1060501183

NCBI 1000 Genomes Browser:

rs1060501183

Molecular consequence:

NM_001005242.3:c.1760A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.1892A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001341572	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19863551, 24704780, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001341572

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 25, 2023)

germline

clinical testing

PubMed (3)
[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

Citations

PubMed

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Barahona-Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R.

Clin Genet. 2010 Jan;77(1):37-48. doi: 10.1111/j.1399-0004.2009.01282.x. Epub 2009 Oct 15.

PubMed [citation]

PMID:: 19863551

Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis.

Rasmussen TB, Nissen PH, Palmfeldt J, Gehmlich K, Dalager S, Jensen UB, Kim WY, Heickendorff L, Mølgaard H, Jensen HK, Baandrup UT, Bross P, Mogensen J.

Circ Cardiovasc Genet. 2014 Jun;7(3):230-40. doi: 10.1161/CIRCGENETICS.113.000338. Epub 2014 Apr 4.

PubMed [citation]

PMID:: 24704780

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001341572.3

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

Description

This missense variant replaces tyrosine with cysteine at codon 631 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with, or suspected of having, arrhythmogenic right ventricular cardiomyopathy (PMID: 19863551, 24704780). In one of these families, the variant was reported not to segregate with the phenotype in the family (PMID: 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: May 1, 2024

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