ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.302G>A (p.Arg101His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(7); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001005242.3(PKP2):c.302G>A (p.Arg101His)
Variation ID: 45076 Accession: VCV000045076.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32878954 (GRCh38) [ NCBI UCSC ] 12: 33031888 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 8, 2015 Jul 23, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.302G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Arg101His missense NM_004572.4:c.302G>A NP_004563.2:p.Arg101His missense NC_000012.12:g.32878954C>T NC_000012.11:g.33031888C>T NG_009000.1:g.22893G>A LRG_398:g.22893G>A LRG_398t1:c.302G>A LRG_398p1:p.Arg101His - Protein change
- R101H
- Other names
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- Canonical SPDI
- NC_000012.12:32878953:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00015
The Genome Aggregation Database (gnomAD) 0.00022
Trans-Omics for Precision Medicine (TOPMed) 0.00033
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PKP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1940 | 1993 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 26, 2023 | RCV000038217.8 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 18, 2021 | RCV000172093.15 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 13, 2024 | RCV000230829.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 18, 2023 | RCV000246062.5 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2020 | RCV000777973.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 14, 2020 | RCV001256846.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Conduction disorder of the heart
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433331.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Likely benign
(Feb 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001785746.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Reported in association with various clinical phenotypes including DCM, ARVC, HCM, and Brugada syndrome (Fressart et al., 2010; Lopes et al., 2013; Pugh et al., … (more)
Reported in association with various clinical phenotypes including DCM, ARVC, HCM, and Brugada syndrome (Fressart et al., 2010; Lopes et al., 2013; Pugh et al., 2014; Allegue et al., 2015); Observed in one individual from a cohort not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death that underwent exome sequencing (Ng et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 45076; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30821013, 27085656, 25351510, 23396983, 23861362, 24503780, 20400443, 26230511) (less)
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Likely benign
(Jan 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001332780.2
First in ClinVar: May 31, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(Jan 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000288606.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Likely benign
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558060.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
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Uncertain significance
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051041.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Likely benign
(Jan 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061885.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
p.Arg101His in exon 2 of PKP2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including … (more)
p.Arg101His in exon 2 of PKP2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the seal and 3 bat species have a histidine (His) at this position despite h igh nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been iden tified in 13/66714 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org/; dbSNP rs149542398). (less)
Number of individuals with the variant: 4
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Uncertain significance
(Nov 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001266942.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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, … (more)
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. (less)
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Likely benign
(Nov 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000914076.2
First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020 |
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Uncertain significance
(Jan 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885972.2
First in ClinVar: Jun 08, 2015 Last updated: Jan 26, 2021 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100157.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: PKP2 c.302G>A (p.Arg101His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PKP2 c.302G>A (p.Arg101His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 282808 control chromosomes (gnomAD), predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00016 vs 0.00065), allowing no conclusion about variant significance. c.302G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g Fressart_2010), Hypertrophic Cardiomyopathy (e.g. Lopes_2013), Dilated Cardiomyopathy (e.g. Pugh_2014) and Brugada Syndrome (e.g. Allegue_2015). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26230511, 30821013, 20400443, 23396983, 24503780). Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, and five as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000319173.8
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.R101H variant (also known as c.302G>A), located in coding exon 2 of the PKP2 gene, results from a G to A substitution at nucleotide … (more)
The p.R101H variant (also known as c.302G>A), located in coding exon 2 of the PKP2 gene, results from a G to A substitution at nucleotide position 302. The arginine at codon 101 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in individuals with Brugada syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy, although many also carried variants in other cardiac-related genes (Pugh TJ et al. Genet Med. 2014;16(8):601-8; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Allegue C et al. PLoS ONE. 2015;10(7):e0133037). In addition, this variant was reported in an individual with arrhythmogenic right ventricular cardiomyopathy who was also homozygous for a DSG2 pathogenic mutation (Fressart V et al. Europace. 2010;12(6):861-8). This variant has also been reported as a secondary cardiac variant of unknown significance in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in one species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Impact of variant reclassification in the clinical setting of cardiovascular genetics. | VanDyke RE | Journal of genetic counseling | 2021 | PMID: 33029862 |
Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. | Campuzano O | Human mutation | 2019 | PMID: 30821013 |
Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families. | Dueker ND | G3 (Bethesda, Md.) | 2018 | PMID: 29288195 |
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. | Yamaguchi-Kabata Y | Journal of human genetics | 2018 | PMID: 29192238 |
Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters. | Miller DC | Stem cell research | 2017 | PMID: 29172153 |
Brugada Syndrome and PKP2: Evidences and uncertainties. | Campuzano O | International journal of cardiology | 2016 | PMID: 27085656 |
Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome. | Allegue C | PloS one | 2015 | PMID: 26230511 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
New insight into the variable expression of arrhythmogenic right ventricular cardiomyopathy provided by the analysis of a plakophilin-2 splice mutation. | Gandjbakhch E | Cardiology | 2012 | PMID: 23183494 |
Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. | Fressart V | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2010 | PMID: 20400443 |
Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Dalal D | Journal of the American College of Cardiology | 2006 | PMID: 17010805 |
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Text-mined citations for rs149542398 ...
HelpRecord last updated Jul 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.