NM_001005242.3(PKP2):c.974C>T (p.Ala325Val) AND Cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 20, 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:: RCV000770421.6

Allele description [Variation Report for NM_001005242.3(PKP2):c.974C>T (p.Ala325Val)]

NM_001005242.3(PKP2):c.974C>T (p.Ala325Val)

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.974C>T (p.Ala325Val)

HGVS:

NC_000012.12:g.32877906G>A
NG_009000.1:g.23941C>T
NM_001005242.3:c.974C>TMANE SELECT
NM_004572.4:c.974C>T
NP_001005242.2:p.Ala325Val
NP_004563.2:p.Ala325Val
NP_004563.2:p.Ala325Val
LRG_398t1:c.974C>T
LRG_398:g.23941C>T
LRG_398p1:p.Ala325Val
NC_000012.11:g.33030840G>A
NM_004572.3:c.974C>T

Protein change:

A325V

Links:

dbSNP: rs201803918

NCBI 1000 Genomes Browser:

rs201803918

Molecular consequence:

NM_001005242.3:c.974C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.974C>T - 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
SCV000901864	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001357948	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31189615, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000901864

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 16, 2016)

germline

clinical testing

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

SCV001357948

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 20, 2022)

germline

clinical testing

PubMed (2)
[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

Suspicion and Persistence: A Case of Pediatric Brugada Syndrome.

Dechert BE, LaPage MJ, Cohen MI.

Pediatrics. 2019 Jul;144(1). doi:pii: e20183296. 10.1542/peds.2018-3296. Epub 2019 Jun 12.

PubMed [citation]

PMID:: 31189615

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

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000901864.1

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

#	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 Color Diagnostics, LLC DBA Color Health, SCV001357948.3

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

Description

This missense variant replaces alanine with valine at codon 325 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome, who also carried a pathogenic variant in the SCN5A gene that could explain the observed phenotype (PMID: 31189615). This variant has also been identified in 12/281476 chromosomes 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: Sep 29, 2024

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