ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.2066_2070del (p.His689fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001005242.3(PKP2):c.2066_2070del (p.His689fs)
Variation ID: 689321 Accession: VCV000689321.23
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 12p11.21 12: 32802500-32802504 (GRCh38) [ NCBI UCSC ] 12: 32955434-32955438 (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 Sep 9, 2019 Apr 20, 2024 Nov 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.2066_2070del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.His689fs frameshift NM_001005242.2:c.2066_2070del NM_001005242.2:c.2066_2070delACACC NM_004572.3:c.2198_2202delACACC NM_004572.4:c.2198_2202del NP_004563.2:p.His733fs frameshift NC_000012.12:g.32802501_32802505del NC_000012.11:g.32955435_32955439del NG_009000.1:g.99343_99347del LRG_398:g.99343_99347del - Protein change
- H689fs, H733fs
- Other names
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- Canonical SPDI
- NC_000012.12:32802499:GGTGTG:G
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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
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The frequency of the allele represented by this VCV record.
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- Links
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 |
1911 | 1964 |
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
Help
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2023 | RCV000850014.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2021 | RCV001559727.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2016 | RCV004017755.1 |
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
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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
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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
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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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Pathogenic
(Dec 01, 2018)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular dysplasia 9
cardiomyopathy diagnosed at autopsy
(more...)
Affected status: yes
Allele origin:
unknown
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Heart Center, Academic Medical Center Amsterdam
Accession: SCV000992156.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
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Pathogenic
(Mar 03, 2015)
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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: SCV001782018.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30700137, 30161220) (less)
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Pathogenic
(Dec 27, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501589.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Mar 30, 2021)
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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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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924230.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
PKP2 NM_004572.3 exon 11 p.His733Alafs*8 (c.2197_2202delinsG): This variant has been reported in the literature in several individuals with ARVC, segregating with disease in at least … (more)
PKP2 NM_004572.3 exon 11 p.His733Alafs*8 (c.2197_2202delinsG): This variant has been reported in the literature in several individuals with ARVC, segregating with disease in at least 4 affected family members (Syrris 2006 PMID:16415378, den Haan 2009 PMID:20031617, Fressart 2010 PMID:20400443, Xu 2010 PMID:20152563, Walsh 2017 PMID:27532257, Hoorntje 2018 PMID:30161220). This variant is not present in large control databases; of note, another variant with a similar amino acid impact (p.His733Profs*8) is present in 0.003% (5/129074) of European controls in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-32955433-GGGTGT-G). This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:45063). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a deletion of 6 nucleotides and an insertion of 1 nucleotide; this indel creates a premature stop codon 8 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Rasmussen 2014 PMID:24704780). In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 07, 2023)
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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:
unknown
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Baylor Genetics
Accession: SCV004183401.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847965.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.His733ProfsX8 variant in PKP2 has not been previously reported in individuals with ARVC or in the large population studies, though a similar variant (His733AlafsX8) … (more)
The p.His733ProfsX8 variant in PKP2 has not been previously reported in individuals with ARVC or in the large population studies, though a similar variant (His733AlafsX8) has been reported in >20 individuals and is classified as pathogenic by our laboratory. This p.His733ProfsX8 rameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 733 and lead to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets our criteria to be classified as pathogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/). (less)
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Pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022278.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_001005242.3:c.2066_2070del (chr12:32802499) in PKP2 was detected in 137 heterozygotes out of 58K WGS Icelanders (MAF= 0,118%). Following imputation in a set of 166K … (more)
The variant NM_001005242.3:c.2066_2070del (chr12:32802499) in PKP2 was detected in 137 heterozygotes out of 58K WGS Icelanders (MAF= 0,118%). Following imputation in a set of 166K Icelanders (305 imputed heterozygotes) we observed an association with atrial fibrillation and flutter using 20168 cases and 351419 controls (OR= 2.31, P= 2.75e-05) and cardiomyopathy using 1974 cases and 365360 controls (OR= 4.11, P= 1.75e-04). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. (less)
Number of individuals with the variant: 305
Ethnicity/Population group: Icelandic
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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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Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. | Miles C | Circulation | 2019 | PMID: 30700137 |
No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy. | Hoorntje ET | PloS one | 2018 | PMID: 30161220 |
Identification of a large set of rare complete human knockouts. | Sulem P | Nature genetics | 2015 | PMID: 25807282 |
Text-mined citations for rs397517021 ...
HelpRecord last updated May 08, 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.