ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1379-1972G>A
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001005242.3(PKP2):c.1379-1972G>A
Variation ID: 239953 Accession: VCV000239953.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32843177 (GRCh38) [ NCBI UCSC ] 12: 32996111 (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 Jul 1, 2016 Aug 18, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005242.3:c.1379-1972G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_004572.4:c.1510+5G>A intron variant NC_000012.12:g.32843177C>T NC_000012.11:g.32996111C>T NG_009000.1:g.58670G>A LRG_398:g.58670G>A LRG_398t1:c.1510+5G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000012.12:32843176: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
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- 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 |
2014 | 2069 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV000232479.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2021 | RCV000603241.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV001177095.6 | |
Uncertain significance (3) |
criteria provided, single submitter
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- | RCV001531777.9 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 18, 2023 | RCV002392702.2 |
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
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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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Uncertain significance
(Dec 29, 2017)
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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: SCV000710873.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.1510+5G>A variant in PKP2 has not been reported in the literature, but was identified in 3/27754 of Latino and 3/91752 of European chromosomes by … (more)
The c.1510+5G>A variant in PKP2 has not been reported in the literature, but was identified in 3/27754 of Latino and 3/91752 of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77939 2697). This variant has also been reported in ClinVar (Variation ID:239953). Thi s variant is located in the 5' splice region. Computational tools suggest some i mpact to splicing. However, this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the c.1510+5G>A varia nt is uncertain. ACMG/AMP Criteria applied: PP3. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jan 26, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000288592.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 6 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. … (more)
This sequence change falls in intron 6 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs779392697, gnomAD 0.01%). This variant has been observed in individual(s) with dilated cardiomyopathy and/or arrhythmogenic cardiomyopathy (PMID: 32826072, 35819174). ClinVar contains an entry for this variant (Variation ID: 239953). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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Uncertain significance
(Nov 15, 2021)
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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: SCV001370650.2
First in ClinVar: Jul 16, 2020 Last updated: Dec 25, 2021 |
Comment:
Variant summary: PKP2 c.1510+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: PKP2 c.1510+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.1e-05 in 181044 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510+5G>A has been reported in the literature in a study of individuals enrolled in MyCode Community Health Initiative of Geisinger Health System (GHS), an IRB-approved research biorepository and precision medicine project (Haggerty_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least two co-occurrences with other pathogenic variant(s) have been reported at our laboratory (HCM-MYBPC3 c.1505G>A, p.Arg502Gln; ARVD-PKP2 c.2509delA, p.Ser837fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(May 28, 2021)
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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: SCV002043313.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Uncertain significance
(May 10, 2023)
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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: SCV001341229.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution at the +5 position of intron 6 of the PKP2 gene. Splice site prediction tools predict that this … (more)
This variant causes a G>A nucleotide substitution at the +5 position of intron 6 of the PKP2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/211564 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Oct 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: SCV002709767.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005191753.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930272.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958592.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management. | Goudal A | Human mutation | 2022 | PMID: 35819174 |
Clinical utility of genetic testing in patients with dilated cardiomyopathy. | Peña-Peña ML | Medicina clinica | 2021 | PMID: 32826072 |
Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. | Ye JZ | Clinical genetics | 2019 | PMID: 31402444 |
Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs779392697 ...
HelpRecord last updated Sep 29, 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.