NM_001005242.3(PKP2):c.302G>A (p.Arg101His) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 13, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000230829.24

Allele description [Variation Report for NM_001005242.3(PKP2):c.302G>A (p.Arg101His)]

NM_001005242.3(PKP2):c.302G>A (p.Arg101His)

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.302G>A (p.Arg101His)

HGVS:

NC_000012.12:g.32878954C>T
NG_009000.1:g.22893G>A
NM_001005242.3:c.302G>AMANE SELECT
NM_004572.4:c.302G>A
NP_001005242.2:p.Arg101His
NP_004563.2:p.Arg101His
NP_004563.2:p.Arg101His
LRG_398t1:c.302G>A
LRG_398:g.22893G>A
LRG_398p1:p.Arg101His
NC_000012.11:g.33031888C>T
NM_004572.3:c.302G>A
c.302G>A

Protein change:

R101H

Links:

dbSNP: rs149542398

NCBI 1000 Genomes Browser:

rs149542398

Molecular consequence:

NM_001005242.3:c.302G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.302G>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

Recent activity

Clear Turn Off Turn On

RecName: Full=Unconventional myosin-XVIIIa; AltName: Full=Molecule associated wi...
RecName: Full=Unconventional myosin-XVIIIa; AltName: Full=Molecule associated with JAK3 N-terminus; Short=MAJN; AltName: Full=Myosin containing a PDZ domain; AltName: Full=Surfactant protein receptor SP-R210; Short=SP-R210
gi|33301318|sp|Q92614.3|MY18A_HUMAN

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000288606	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 13, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20400443, 23861362, 24503780, 25351510, 26230511, 28492532
SCV000885972	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jan 20, 2020)	germline	clinical testing	Citation Link,
SCV001266942	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Nov 21, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26230511, 24503780, 27085656, 20400443 Citation Link,
SCV002558060	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Feb 2, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17010805, 20400443, 23183494, 23396983, 23861362, 24503780, 26230511, 25741868

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

Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.

Lopes LR, Syrris P, Guttmann OP, O'Mahony C, Tang HC, Dalageorgou C, Jenkins S, Hubank M, Monserrat L, McKenna WJ, Plagnol V, Elliott PM.

Heart. 2015 Feb;101(4):294-301. doi: 10.1136/heartjnl-2014-306387. Epub 2014 Oct 28.

PubMed [citation]

PMID:: 25351510
PMCID:: PMC4345808

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 (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000288606.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 101 of the PKP2 protein (p.Arg101His). This variant is present in population databases (rs149542398, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy, Brugada syndrome and dilated cardiomyopathy (PMID: 20400443, 23861362, 24503780, 25351510, 26230511). ClinVar contains an entry for this variant (Variation ID: 45076). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885972.2

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

Description

The p.Arg101His variant (rs149542398) has been observed in several cohorts of cardiomyopathy patients (selected references: Allegue 2015, Fressart 2010, Pugh 2014) and one control cohort (Ng 2013); however, specific clinical information and segregated data were not provided. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.034% (identified in 43 out of 126,664 chromosomes). It is also listed in the ClinVar database (Variation ID: 45076). The arginine at codon 101 is weakly conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg101His variant cannot be determined with certainty.

#	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 Illumina Laboratory Services, Illumina, SCV001266942.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002558060.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (ARVD9; MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, PMID: 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 17010805, PMID: 23183494). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (46 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes each). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely benign in ClinVar and as VUS in multiple individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy and Brugada syndrome (ClinVar, PMID: 20400443, 23396983, 24503780, 26230511), and also reported in an unaffected control individual (PMID: 23861362). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

ClinVar

Relating variation to medicine