MBL2 G57E - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

MBL2 G57E

(MBL2 Gly57Glu)


Short summary

This variant is associated with mannose binding protein deficiency which leads to impaired complement system immune response to mannose-rich pathogens. The wild-type version of this gene is known as variant allele A, while this is called variant allele C. See R52C (variant D) and G54D (variant B).

Variant evidence
Computational 5

NBLOSUM=4, gene associated with disease, expected to disrupt secondary structure
Variant Effect Predictor (Ensembl ):
SIFT=deleterious(0);
PolyPhen=probably_damaging(0.999);
Condel=deleterious(0.999)
Mutation Tasting Prediction: Polymorphism p value: 0.007512
protein features (might be) affected (Detail: 42-99 DOMAIN Collagen-like gets lost)
GVGD: GV 0.00; GD 97.85; Class C65
Multi-alignment P11226.2 mannose-binding protein C precursor [Homo sapiens] with: Q66S60.1 [Gorilla gorilla] NP_001009005.1 [Pan troglodytes] AAX84955.1 [Gorilla gorilla] AAX84956.1 [Pongo pygmaeus] XP_002820974.1 [Pongo pygmaeus] Q66S37.1 [Chlorocebus aethiops] Q66S54.1 [Hylobates lar] Q66S58.1 [Nomascus concolor] AAX84957.1 [Papio hamadryas] NP_001099005.1 [Macaca mulatta]

See Lipscombe RJ et al. 1992 (1304173).

Functional -
Case/Control

Case control evidence is poor, possibly because this variant is rare.

See Garred P et al. 1995 (7564730), Hibberd ML et al. 1999 (10199352), unpublished research (below).

Familial

No familial evidence.

 
Clinical importance
Severity 1

Increased susceptibility to infection, but little effect (if any) noted for this variant

Treatability 1

No specific treatment, routine vaccinations recommended.

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Mannose-Binding Lectin Deficiency
2 493 3 505 1.0000 0.683

 

Allele frequency

  • T @ chr10:54531226: 9.2% (986/10758) in EVS
  • T @ chr10:54201231: 6.3% (8/126) in GET-Evidence
  • Frequency shown in summary reports: 9.2% (986/10758)

Publications
 

Lipscombe RJ, Sumiya M, Hill AV, Lau YL, Levinsky RJ, Summerfield JA, Turner MW. High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum Mol Genet. 1992 Dec;1(9):709-15. Erratum in: Hum Mol Genet 1993 Mar;2(3):342. PubMed PMID: 1304173.

This variant was discovered through sequencing exon 1 in mannose binding protein deficient Ghanian newborns where 10 newborns homozygous for this variant has no detectable levels. The frequencies were 0.29 (Ghanian adult), 0.23 (Ghanian newborn). Similar to the G54D mutation (0.17, British Caucasian and 0.11 Hong Kong), this variant disrupts the secondary structure of the protein, and is predicted to reduce the immune response to Mannose-rich organisms in infancy.

Garred P, Madsen HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency. Lancet. 1995 Oct 7;346(8980):941-3. PubMed PMID: 7564730.

A study of patients with suspected immunodeficiency found a higher number of homozygous and compound heterozygous patients with abnormal mannan-binding protein (MBP) alleles (variants B, C, and D). In the case group of 229 patients, none were homozygous for C and one was compound heterozygous for B/C. No patients in the control population of 123 controls were homozygous or compound heterozygous for this allele.

Cases/controls case+ case– control+ control– p-value odds ratio
Mannose-Binding Lectin Deficiency
1 228 0 123 1.0000

 

Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet. 1999 Mar 27;353(9158):1049-53. PubMed PMID: 10199352.

In a study of meningcoccal susceptibility in a British population of children, patients were assayed for abnormal variants of MBL2. Of 266 patients, none were homozygous for G57E and one was compound heterozygous for G57E and R52C. Of 382 controls, one was homozygous for G57E and two were compound heterozygous. Although the paper supports pathogenicity for R52C and G54D variants, the evidence does not seem to support this particular variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Mannose-Binding Lectin Deficiency
1 265 3 382 0.6486 0.481

 

Milanese M, Segat L, De Seta F, Pirulli D, Fabris A, Morgutti M, Crovella S. MBL2 genetic screening in patients with recurrent vaginal infections. Am J Reprod Immunol. 2008 Feb;59(2):146-51. PubMed PMID: 18211540.

Authors screen for MBL2 polymorphisms in patients with recurrent vaginal infections and find no significant differences between the groups.

Dorfman R, Sandford A, Taylor C, Huang B, Frangolias D, Wang Y, Sang R, Pereira L, Sun L, Berthiaume Y, Tsui LC, Paré PD, Durie P, Corey M, Zielenski J. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest. 2008 Mar;118(3):1040-9. PubMed PMID: 18292811; PubMed Central PMCID: PMC2248329.

In a study of 1019 Canadians with cystic fibrosis for complex gene interactions leading to increased lung disease, low MBL2 levels (caused by this variant and others) were significantly associated with earlier onset of lung infection.

Genomes
 

 

GS18508 - var-GS18508-1100-36-ASM
het T @ chr10:54201232

 

GS18517 - var-GS18517-1100-36-ASM
het T @ chr10:54201232

 

GS19020 - var-GS19020-1100-36-ASM
het T @ chr10:54201232

 

GS19239 - var-GS19239-1100-36-ASM
het T @ chr10:54201232

 

GS19240 - var-GS19240-1100-36-ASM
hom T @ chr10:54201232

 

GS19649 - var-GS19649-1100-36-ASM
het T @ chr10:54201232

 

GS19703 - var-GS19703-1100-36-ASM
het T @ chr10:54201232

 

GS19704 - var-GS19704-1100-36-ASM
het T @ chr10:54201232

 

Other external references
 

    dbSNP
  • rs1800451
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.999 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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