Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: PLG

I don't know

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:59 a.m. | Last Modified: 8 Mar 2022, 10:59 a.m.

Panel Version: 2.532

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

• 28795768
• 29548426
• 29952006
• 30809376
• 31131012
• 32066472
• 32065705
• 32181895
• 33799813

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

• 28795768
• 29548426
• 29987869

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

• PMID: 28795768