NM_001005242.3(PKP2):c.1367A>C (p.Lys456Thr) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV000535469.10

Allele description [Variation Report for NM_001005242.3(PKP2):c.1367A>C (p.Lys456Thr)]

NM_001005242.3(PKP2):c.1367A>C (p.Lys456Thr)

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.1367A>C (p.Lys456Thr)

HGVS:

NC_000012.12:g.32850777T>G
NG_009000.1:g.51070A>C
NM_001005242.3:c.1367A>CMANE SELECT
NM_004572.4:c.1367A>C
NP_001005242.2:p.Lys456Thr
NP_004563.2:p.Lys456Thr
NP_004563.2:p.Lys456Thr
LRG_398t1:c.1367A>C
LRG_398:g.51070A>C
LRG_398p1:p.Lys456Thr
NC_000012.11:g.33003711T>G
NM_004572.3:c.1367A>C

Protein change:

K456T

Links:

dbSNP: rs750897570

NCBI 1000 Genomes Browser:

rs750897570

Molecular consequence:

NM_001005242.3:c.1367A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.1367A>C - 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
SCV000638863	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34120153, 28492532
SCV002792284	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 21, 2021)	unknown	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

SCV000638863

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 21, 2023)

germline

clinical testing

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

SCV002792284

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 21, 2021)

unknown

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The genetic architecture of Plakophilin 2 cardiomyopathy.

Dries AM, Kirillova A, Reuter CM, Garcia J, Zouk H, Hawley M, Murray B, Tichnell C, Pilichou K, Protonotarios A, Medeiros-Domingo A, Kelly MA, Baras A, Ingles J, Semsarian C, Bauce B, Celeghin R, Basso C, Jongbloed JDH, Nussbaum RL, Funke B, Cerrone M, et al.

Genet Med. 2021 Oct;23(10):1961-1968. doi: 10.1038/s41436-021-01233-7. Epub 2021 Jun 12. Erratum in: Genet Med. 2021 Oct;23(10):2014. doi: 10.1038/s41436-021-01298-4.

PubMed [citation]

PMID:: 34120153
PMCID:: PMC8486657

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638863.6

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

Description

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 456 of the PKP2 protein (p.Lys456Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sudden cardiac death (PMID: 34120153). ClinVar contains an entry for this variant (Variation ID: 464411). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792284.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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