SERPINA1 E366K - GET-Evidence

Curation:

(See latest approved version)
Currentness:

SERPINA1 E366K

(SERPINA1 Glu366Lys)


Short summary

This is also called the “Pi Z” or “Z” allele. When homozygous (acting in a recessive manner) this variant is the major cause of severe alpha-1-antitrypsin deficiency (95% of cases) which often leads to emphysema or chronic obstructive pulmonary disease (COPD) and liver disease in adults and children. Heterozygosity for this variant may also be associated with increased rate of lung or liver problems, especially when combined with another variant with reduced function (compound heterozygous).

Variant evidence
Computational 2

This gene is associated with disease, polyphen 2 predicts damaging effect

Functional 1

16% wildtype plasma concentration

See Jeppsson JO et al. 1982 (6976856).

Case/Control 5

This is a well established causative variant

See Fregonese L et al. 2008 (18565211).

Familial 5

Well established cause of hereditary alpha-1-antitrypsin deficiency

See Fregonese L et al. 2008 (18565211).

 
Clinical importance
Severity 4

Causes an increased risk of lung and liver problems.

Treatability 3

Avoidance of damaging inhalants and other treatments help to reduce the effect of this disease.

Penetrance 4

Moderate or high penetrance for emphysema / chronic obstructive pulmonary disease

 

Impact

High clinical importance, pathogenic

(The "high clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

This variant represents the PiZ variant of Alpha-1-antitrypsin. PiZZ genotype has Alpha-1-antitrypsin levels 10-15% of normal and has Alpha-1-antitrypsin deficiency, a heterozygote has 60% of normal enzymatic activity. 95% of A1ATD is caused by the PiZZ phenotype (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alpha1-a#alpha1-a.Diagnosis), and smoking and alcohol consumption increase risk of lung and liver diseases.

Allele frequency

  • T @ chr14:94844947: 1.2% (126/10758) in EVS
  • T @ chr14:93914699: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.2% (126/10758)

Publications
 

Jeppsson JO, Franzén B. Typing of genetic variants of alpha 1-antitrypsin by electrofocusing. Clin Chem. 1982 Jan;28(1):219-25. PubMed PMID: 6976856.

The PiZZ variant shows a mean plasma concentration 16% of wildtype.

Luisetti M, Massi G, Massobrio M, Guarraci P, Menchicchi FM, Beccaria M, Balbi B. A national program for detection of alpha 1-antitrypsin deficiency in Italy. Gruppo I.D.A. Respir Med. 1999 Mar;93(3):169-72. PubMed PMID: 10464873.

 

Lee PL, West C, Crain K, Wang L. Genetic polymorphisms and susceptibility to lung disease. J Negat Results Biomed. 2006 Apr 11;5:5. PubMed PMID: 16608528; PubMed Central PMCID: PMC1475880.

This group found that the variant has no effect on lung disease (singly). Controls w/ variant 4/192 and cases w/variant 2/190.

de la Roza C, Lara B, Vilà S, Miravitlles M. [Alpha1-antitrypsin deficiency: situation in Spain and development of a screening program]. Arch Bronconeumol. 2006 Jun;42(6):290-8. Review. Spanish. PubMed PMID: 16827978.

In this review of the literature, the increased risk for the heterozygote developing chronic obstructive pulmonary disease is discussed (OR can be as high as 5).

Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008 Jun 19;3:16. Review. PubMed PMID: 18565211; PubMed Central PMCID: PMC2441617.

 

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr14:94844947

This individual has the PiSZ genotype, placing him at increased risk for Alpha-1-antitrypsin deficiency. Smoking and alcohol consumption should be limited.

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het T @ chr14:94844947

 

Other external references
 

    dbSNP
  • rs28929474
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 1.0 (probably damaging)
    Web search results (6 hits -- see all)
  • An Improved Approach to Diagnosis of α α 1-Antitrypsin Deficiency
    for glutamic acid at codon 366 (E366K). This. mutation acts as both a deficiency and a ... gene=serpina1;jsessionid=2F91D1EF6AADE481D03 BCC3F3BA8B429. 5. Snyder MR, Katzmann JA, ...
    mayomedicallaboratories.com/.../communique/mc2831-1006.pdf
  • Table 3
    AAT (SERPINA1) dbSNP rs# SNP. amino acid. Control. Lung Disease. Power to detect 2× increase ... E366K. 4/192 (0.02) 2/190 (0.01) 0.07. Lee et al. Journal of Negative ...
    www.jnrbm.com/content/5/1/5/table/T3
  • Genetic polymorphisms and susceptibility to lung disease
    AAT (SERPINA1) dbSNP rs# SNP. amino acid. Control. Lung Disease. Power to ... AAT S (Glu288Val) and Z (E366K) alleles, associated with chronic obstructive ...
    www.biomedcentral.com/content/download/xml/1477-5751-5-5.xml
  • Journal of Negative Results in BioMedicine
    and Z (E366K) alleles, associated with chronic obstructive. lung disease, were examined ... (SERPINA1) dbSNP rs# SNP. amino acid. Control. Lung Disease. Power to ...
    www.biomedcentral.com/content/pdf/1477-5751-5-5.pdf
  • Molekulaargeneetilised uuringud sisekliinikus
    nn Z alleeli (PI*Z ehk p.E366K) suhtes. SERPINA1 asub 14q32.13, suurus 14kb, koosneb 7 ... allikates S ja Z alleelide positsioonid erinevad: E366K=E342K; E288V=E264V ...
    elmy.ee/public/files/T.Kahre - Geneetilised uuringud sise...
  • Real time PCR detection of the PI*Z and PI*S mutations ...
    Mutations in the SERPINA1 gene can result in both early onset chronic ... to a glutamic acid to lysine substitution at amino acid 366 (E366K; rs28929474) ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2780033

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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