ClinVar Genomic variation as it relates to human health
NM_000301.5(PLG):c.988A>G (p.Lys330Glu)
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_000301.5(PLG):c.988A>G (p.Lys330Glu)
Variation ID: 590291 Accession: VCV000590291.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q26 6: 160718730 (GRCh38) [ NCBI UCSC ] 6: 161139762 (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 Apr 29, 2019 Feb 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000301.5:c.988A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000292.1:p.Lys330Glu missense NC_000006.12:g.160718730A>G NC_000006.11:g.161139762A>G NG_016200.1:g.21538A>G LRG_571:g.21538A>G LRG_571t1:c.988A>G LRG_571p1:p.Lys330Glu - Protein change
- K330E
- Other names
- chr6:161139762A>G
- Canonical SPDI
- NC_000006.12:160718729:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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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PLG | - | - |
GRCh38 GRCh37 |
383 | 422 |
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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Pathogenic (1) |
no assertion criteria provided
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Aug 6, 2018 | RCV000768407.2 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 15, 2022 | RCV001507288.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV001862090.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 30, 2023 | RCV003420282.4 |
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 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Angioedema, hereditary, 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002762862.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Clinical Features:
Hypertensive disorder (present) , Edema (present) , Osteomyelitis (present) , Abnormality of fluid regulation (present) , Angioedema (present)
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Pathogenic
(Apr 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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PLG-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114206.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PLG c.988A>G variant is predicted to result in the amino acid substitution p.Lys330Glu. This variant, also known as K330E, has been reported in many … (more)
The PLG c.988A>G variant is predicted to result in the amino acid substitution p.Lys330Glu. This variant, also known as K330E, has been reported in many individuals with hereditary angioedema with normal C1 inhibitor (HAEnCI) (Bork K et al 2017. PubMed ID: 28795768; Dewald et al 2018. PubMed ID: 29548426; Belbézier A et al 2018. PubMed ID: 29952006; Yakushiji H et al 2018. PubMed ID: 29987869; Bork K et al 2020. PubMed ID: 32065705; Parsopoulou F et al 2020. PubMed ID: 32181895). This variant was observed to segregate with disease in at least a few families while showing incomplete penetrance. Functional studies revealed that this variant leads to altered PLG glycosylation and increased sensitivity to plasminogen activators (Dewald et al 2018. PubMed ID: 29548426; Parsopoulou F et al 2020. PubMed ID: 32181895) This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-161139762-A-G). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002228205.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 330 of the PLG protein … (more)
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 330 of the PLG protein (p.Lys330Glu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with hereditary angioedema (PMID: 28795768, 29548426). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1100A>G (p.Lys311Glu). ClinVar contains an entry for this variant (Variation ID: 590291). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLG protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 06, 2018)
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no assertion criteria provided
Method: research
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Hereditary angioneurotic edema
Affected status: yes
Allele origin:
germline
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ITMI
Accession: SCV000844988.1
First in ClinVar: Apr 29, 2019 Last updated: Apr 29, 2019 |
Clinical Features:
Angioedema (present)
Sex: female
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Pathogenic
(Sep 12, 2022)
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no assertion criteria provided
Method: literature only
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ANGIOEDEMA, HEREDITARY, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001712260.4
First in ClinVar: Jun 15, 2021 Last updated: Sep 17, 2022 |
Comment on evidence:
Note: A c.1100A-G transtion (NM_0003013.3), resulting in a lys311-to-glu (K311E) substitution of the mature protein, corresponds to c.988A-G (K300E) if nucleotide numbering starts with the … (more)
Note: A c.1100A-G transtion (NM_0003013.3), resulting in a lys311-to-glu (K311E) substitution of the mature protein, corresponds to c.988A-G (K300E) if nucleotide numbering starts with the A of the ATG translation initiation codon (Dewald, 2018). In 60 patients from 13 unrelated families of European descent with hereditary angioedema-4 (HAE4; 619360), Bork et al. (2018) identified a heterozygous c.988A-G transition (c.988A-G, NM_000301) in exon 9 of the PLG gene, resulting in a lys330-to-glu (K330E) substitution at a conserved residue in the kringle 3 domain. The mutation, which was found by whole-exome sequencing or next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was some evidence for incomplete penetrance. This numbering is based on the primary translation product. This variant was not present in the dbSNP, ExAC, or 1000 Genomes Project databases; it was found once in gnomAD (1 in 31,591 alleles in the European population). Functional studies of the variant and studies of patient cells were not performed, but 3 patients studied had normal plasminogen activity. The authors postulated a founder effect. In 18 patients from 3 unrelated multigenerational German families with HAE4, Dewald (2018) identified the heterozygous K330E mutation in the PLG gene. The authors stated that this was a c.1100A-G transition, resulting in a lys311-to-glu (K311E) substitution in the mature protein. Isoelectric focusing of patient plasma identified aberrant PLG protein bands that were different from controls. The findings suggested that the mutation caused some quantitative and qualitative effects on the glycosylation of plasminogen. The K330E substitution is located in the kringle 3 domain important for binding that enables plasminogen or plasmin to interact with other protein ligands. This residue is conserved in humans, but is a glutamic acid residue in all other species examined, suggesting that the mutation actually reverses the evolution of the human K3 sequence and corresponds to the reappearance of the ancestral amino acid state. Functional studies of the variant and studies of patient cells were not performed, but Dewald (2018) speculated that the mutation could affect the affinity of binding partners and thus have functional consequences, particularly on the kinin pathway that regulates circulating vasoactive substances. Yakushiji et al. (2018) identified a heterozygous K330E mutation in 4 affected patients from 2 unrelated Japanese families. Functional studies of the variant were not performed, but the report confirmed that this mutation can be found in various ethnic populations. The mutations were found by direct sequencing of exon 9 of the PLG gene in 20 unrelated Japanese probands with HAE and normal C1INH levels. Belbezier et al. (2018) identified the K330E mutation in 10 patients from 3 unrelated French families with HAE4. Functional studies of the variant and studies of patient cells were not performed. The patients were part of a cohort of 15 families who underwent genetic testing, thus accounting for 20%. Farkas et al. (2021) reported a 60-year-old woman (patient E385) with HAE and the K330E mutation. The patient was identified from 124 patients with HAE of unknown origin whose cells were in a repository and were tested retrospectively. Her son, who also carried the common K330E mutation in the PLG gene, was asymptomatic. Functional studies of the variant were not performed, but the authors speculated that this variant in the PLG gene results in enhanced activation of the fibrinolytic system, with the generation of plasmin, activation of the kinin-kallikrein system, and bradykinin release. Dickeson et al. (2022) purified wildtype PLG and mutant PLG with the K311E mutation following expression in Expi293 cells. When tPA was added to normal plasma that was supplemented with either wildtype or K311E PLG, bradykinin (BK) generation was significantly higher with K311E. This increased generation of BK was not dependent on prekallikrein or factor XII (F12; 610619). K311E was also shown to liberate BK from both high and low molecular weight kininogens (HK and LK) faster than wildtype. Dickeson et al. (2022) concluded that K311E contributes to angioedema by directly catalyzing kinin release from HK and LK. (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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A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen. | Dickeson SK | Blood | 2022 | PMID: 35100351 |
Screening for Plasminogen Mutations in Hereditary Angioedema Patients. | Farkas H | Genes | 2021 | PMID: 33799813 |
Genotype-first analysis of a generally healthy population cohort supports genetic testing for diagnosis of hereditary angioedema of unknown cause. | Bodian DL | Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology | 2019 | PMID: 31131012 |
A missense mutation of the plasminogen gene in hereditary angioedema with normal C1 inhibitor in Japan. | Yakushiji H | Allergy | 2018 | PMID: 29987869 |
Plasminogen gene mutation with normal C1 inhibitor hereditary angioedema: Three additional French families. | Belbézier A | Allergy | 2018 | PMID: 29952006 |
A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor. | Dewald G | Biochemical and biophysical research communications | 2018 | PMID: 29548426 |
Hereditary angioedema with a mutation in the plasminogen gene. | Bork K | Allergy | 2018 | PMID: 28795768 |
Text-mined citations for rs889957249 ...
HelpRecord last updated Mar 11, 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.