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Primary immunodeficiency

Gene: PLG

Amber List (moderate evidence)

PLG (plasminogen)
EnsemblGeneIds (GRCh38): ENSG00000122194
EnsemblGeneIds (GRCh37): ENSG00000122194
OMIM: 173350, Gene2Phenotype
PLG is in 8 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: Discussed with Helen Brittain (Genomics England Clinical Team) regarding the reduced penetrance and recurrence of the angioedema-specific variant (c.988A>G, p.K330E) in this gene - 'it goes slightly against our usual rule of needing another source to corroborate that it is the variant itself, but the evidence is reasonably compelling and this is harder if there happens to be a narrow pathogenic variant spectrum e.g. gain of function missense. In view of the reduced penetrance, and this slight doubt, I would prefer to ask the opinion of the evaluation working group'

Therefore rating Amber with the recommendation of expert review at the next GMS panel update (tagged)

Note: this phenotype is also now listed in OMIM (MIM# 619360)
Created: 27 Jul 2021, 10:51 a.m. | Last Modified: 27 Jul 2021, 11:21 a.m.
Panel Version: 2.450
Penetrance for PLG on this panel was set from 'unknown' to 'incomplete'
Created: 27 Jul 2021, 10:41 a.m. | Last Modified: 27 Jul 2021, 10:42 a.m.
Panel Version: 2.447
Bork et al. 2018 (PMID: 28795768) found a recurrent variant (c.988A>G, p.K330E) in 13 German families with hereditary angioedema. However, the variant is associated with incomplete penetrance as there are several asymptomatic carriers within the families and the variant can be found at low freq in the European population in gnomAD - but has been classified as 'Pathogenic'.

There is no evidence of other relevant variants but this seems to be an accepted causal variant in the literature and several subsequent publications have identified additional cases (PMIDs: 29548426; 29952006; 30809376; 31131012; 32066472; 32065705; 32181895; 33799813). Most cases are of European ancestry and haplotype analysis performed by the original study (Bork et al. 2018) indicated a likely founder effect. However, 2 families in Japan have since been identified indicating the variant may be found in various ethnic populations (PMID: 29987869)

There is some data that suggests the variant might affect plasminogen glycosylation (PMIDs: 29548426; 32181895), however multiple patients have also been identified with normal plasminogen activity.
Created: 27 Jul 2021, 10:38 a.m. | Last Modified: 27 Jul 2021, 11:17 a.m.
Panel Version: 2.449

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Angioedema, hereditary, 4, OMIM:619360

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Association between mono-allelic variants and HAE: Over 20 families reported with a recurrent variant, p.Lys330Glu. Single family reported with a different variant. Note bi-allelic variants are associated with a separate disorder.
Created: 11 Jun 2021, 10:37 a.m. | Last Modified: 11 Jun 2021, 10:37 a.m.
Panel Version: 2.427

Phenotypes
Hereditary angioedema-4 (HAE4), MIM#619360

Publications

Matthew Buckland (Great Ormond Street Hospital for Children NHS Foundation Trust)

Green List (high evidence)

Bork et al. identified the exon9 mutation in PLG in four index families with normal-C1 hereditary angioedema and a further 9 families studied, with shared clinical features.
Sufficient information to ascribe causality.
Sources: Literature
Created: 4 May 2021, 11:22 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Non-C1 Hereditary Angioedema

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Angioedema, hereditary, 4, OMIM:619360
Tags
Q2_21_NHS_review Q3_21_expert_review
OMIM
173350
Clinvar variants
Variants in PLG
Penetrance
Incomplete
Publications
Panels with this gene

History Filter Activity

27 Jul 2021, Gel status: 2

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag founder-effect was removed from gene: PLG.

27 Jul 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: PLG were set to 28795768; 29548426; 29987869; 31131012; 32066472; 32065705; 32181895

27 Jul 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: PLG were set to PMID: 28795768

27 Jul 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: plg has been classified as Amber List (Moderate Evidence).

27 Jul 2021, Gel status: 0

Set penetrance

Arina Puzriakova (Genomics England Curator)

Penetrance for gene PLG was set from to unknown

27 Jul 2021, Gel status: 0

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag founder-effect tag was added to gene: PLG. Tag Q3_21_expert_review tag was added to gene: PLG.

27 Jul 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PLG were changed from Angioedema, hereditary, 4, OMIM:619360 to Angioedema, hereditary, 4, OMIM:619360

27 Jul 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PLG were changed from Non-C1 Hereditary Angioedema to Angioedema, hereditary, 4, OMIM:619360

8 Jun 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_21_NHS_review tag was added to gene: PLG.

4 May 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Matthew Buckland (Great Ormond Street Hospital for Children NHS Foundation Trust)

gene: PLG was added gene: PLG was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: PLG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLG were set to PMID: 28795768 Phenotypes for gene: PLG were set to Non-C1 Hereditary Angioedema Penetrance for gene: PLG were set to unknown Review for gene: PLG was set to GREEN