NM_001005242.3(PKP2):c.1726G>A (p.Ala576Thr) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 26, 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:: RCV003829586.2

Allele description [Variation Report for NM_001005242.3(PKP2):c.1726G>A (p.Ala576Thr)]

NM_001005242.3(PKP2):c.1726G>A (p.Ala576Thr)

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.1726G>A (p.Ala576Thr)

HGVS:

NC_000012.12:g.32822580C>T
NG_009000.1:g.79267G>A
NM_001005242.3:c.1726G>AMANE SELECT
NM_001407155.1:c.1726G>A
NM_001407156.1:c.1675-1051G>A
NM_001407157.1:c.1858G>A
NM_001407158.1:c.1399G>A
NM_001407159.1:c.1399G>A
NM_001407160.1:c.1399G>A
NM_001407161.1:c.1726G>A
NM_001407162.1:c.1399G>A
NM_004572.4:c.1858G>A
NP_001005242.2:p.Ala576Thr
NP_001394084.1:p.Ala576Thr
NP_001394086.1:p.Ala620Thr
NP_001394087.1:p.Ala467Thr
NP_001394088.1:p.Ala467Thr
NP_001394089.1:p.Ala467Thr
NP_001394090.1:p.Ala576Thr
NP_001394091.1:p.Ala467Thr
NP_004563.2:p.Ala620Thr
NP_004563.2:p.Ala620Thr
LRG_398t1:c.1858G>A
LRG_398:g.79267G>A
LRG_398p1:p.Ala620Thr
NC_000012.11:g.32975514C>T
NM_004572.3:c.1858G>A

Protein change:

A467T

Molecular consequence:

NM_001407156.1:c.1675-1051G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001005242.3:c.1726G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407155.1:c.1726G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407157.1:c.1858G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407158.1:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407159.1:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407160.1:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407161.1:c.1726G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407162.1:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.1858G>A - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004628522	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004628522

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2023)

germline

clinical testing

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004628522.1

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 620 of the PKP2 protein (p.Ala620Thr). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.

#	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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