SERPINA1 E288V - GET-Evidence

Curation:

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Currentness:

SERPINA1 E288V

(SERPINA1 Glu288Val)


Short summary

This variant represents the PiS variant in alpha-1-antitrypsin deficiency where a homozygous individual has 60% enzymatic activity. This variant alone is unlikely to much effect, but 3-4% of heterozygotes are compound heterozygous with the more severe PiZ variant, which is associated with an increased risk of emphysema and COPD.

Variant evidence
Computational 3

The gene is associated with this disease, NBLOSUM=3, polyphen 2 predicts damaging effect

Functional 1

Unstable protein

See Long GL et al. 1984 (6093867), Fregonese L et al. 2008 (18565211).

Case/Control 5

Well stablished

See Mahadeva R et al. 1999 (10194472), Hadzic N et al. 2005 (15711957), Bartels CL et al. 2009 (19956452).

Familial -
 
Clinical importance
Severity 2

Homozygosity for this variant alone does not have much increased risk for disease, but may cause increased risk of lung disease if compound heterozygous with PiZ

Treatability 3
Penetrance 1

Homozygosity for this gene alone does not have much (if any) effect, but can cause increased risk disease when compound heterozygous with PiSZ (~3-4% of heterozygotes)

 

Impact

Low clinical importance, pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

E288V and E366K comprise the PiS and PiZ variants of Alpha 1-antitrypsin. An individual heterozygous or homozygous at these two positions is at increased risk for Alpha-1-antitrypsin deficiency.

Allele frequency

  • A @ chr14:94847262: 3.0% (328/10758) in EVS
  • A @ chr14:93917014: 4.7% (6/128) in GET-Evidence
  • Frequency shown in summary reports: 3.0% (328/10758)

Publications
 

Long GL, Chandra T, Woo SL, Davie EW, Kurachi K. Complete sequence of the cDNA for human alpha 1-antitrypsin and the gene for the S variant. Biochemistry. 1984 Oct 9;23(21):4828-37. PubMed PMID: 6093867.

 

Turino GM, Barker AF, Brantly ML, Cohen AB, Connelly RP, Crystal RG, Eden E, Schluchter MD, Stoller JK. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1718-25. PubMed PMID: 8970361.

 

Mahadeva R, Chang WS, Dafforn TR, Oakley DJ, Foreman RC, Calvin J, Wight DG, Lomas DA. Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. J Clin Invest. 1999 Apr;103(7):999-1006. PubMed PMID: 10194472; PubMed Central PMCID: PMC408255.

 

Hadzic N, Francavilla R, Chambers SM, Castellaneta S, Portmann B, Mieli-Vergani G. Outcome of PiSS and PiSZ alpha-1-antitrypsin deficiency presenting with liver involvement. Eur J Pediatr. 2005 Apr;164(4):250-2. Epub 2005 Feb 15. PubMed PMID: 15711957.

 

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 5/192 and cases w/variant 4/190.

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.

This variant represents the PiS variant in alpha-1-antitrypsin deficiency where a homozygous individual has 60% enzymatic activity. The authors cite Long et al and write that “the homozygous S variant of alpha-1-antitrypsin results in an instable protein that is easily degraded outside the hepatocyte and affects the half-life of the S variant.”

Bartels CL, Marchetti AL, Edward Highsmith W, Tsongalis GJ. Real time PCR detection of the PI*Z and PI*S mutations associated with alpha-1 antitrypsin deficiency. Am J Transl Res. 2009 Aug 10;1(4):406-11. PubMed PMID: 19956452; PubMed Central PMCID: PMC2780033.

“The most common variant associated with clinical disease is PI*Z allele which results from a G to an A transition at nucleotide position 11940 in exon 5 and leads to a glutamic acid to lysine substitution at amino acid 366 (E366K; rs28929474). The PI*S allele results from an A to T transversion at nucleotide position 9628 in exon 3 and leads to a glutamic acid to valine substitution at amino acid 288 (E288V; rs17580) [13, 14]. Older literature, which uses an amino acid numbering convention based on the mature, processed protein, refers to these mutations as E342K and E264V, respectively. A genotype of ZZ or SZ can cause clinical AAT deficiency, but the homozygous Z genotype typically results in the most severe clinical phenotype. “

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr14:94847262

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

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr14:94847262

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr14:94847262

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr14:94847262

 

GS06994 - var-GS06994-1100-36-ASM
het A @ chr14:93917015

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr14:93917015

 

Other external references
 

    dbSNP
  • rs17580
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.995 (probably damaging)
    Web search results (8 hits -- see all)
  • An Improved Approach to Diagnosis of α α 1-Antitrypsin Deficiency
    for glutamic acid at codon 288 (E288V). This change. results in intracellular A1AT ... gene=serpina1;jsessionid=2F91D1EF6AADE481D03 BCC3F3BA8B429 ...
    mayomedicallaboratories.com/.../communique/mc2831-1006.pdf
  • Table 3
    AAT (SERPINA1) dbSNP rs# SNP. amino acid. Control. Lung Disease. Power to detect 2× increase ... E288V. 5/190 (0.03) 4/190 (0.02) 0.1. Exon 4. rs28929474. 1096G/A. E366K. 4 ...
    www.jnrbm.com/content/5/1/5/table/T3
  • Journal of Negative Results in BioMedicine
    individuals of the AAT S allele (E288V) are not at risk for. emphysema but compound ... (SERPINA1) dbSNP rs# SNP. amino acid. Control. Lung Disease. Power to ...
    www.biomedcentral.com/content/pdf/1477-5751-5-5.pdf
  • Genetic polymorphisms and susceptibility to lung disease
    LeeLPaulineplee@scripps.eduWestCarolcwest@scripps.eduCrainKarenkcrain@scripps. ... individuals of the AAT S allele (E288V) are not at risk for emphysema but ...
    www.biomedcentral.com/content/download/xml/1477-5751-5-5.xml
  • Table 3 Text
    member 1" 24 rs1303 SERPINA1 5265 14 93914596 NM_000295 NP_000286 G/T E400D ... rs1303 SERPINA1 5265 14 93914596 NM_000295 NP_000286 G/T E400D plus 16651029 ...
    icr.ac.uk/research/research_sections/.../2842.txt
  • Molekulaargeneetilised uuringud sisekliinikus
    AAT puudulikkuse põhjuseks on SERPINA1 (anti-elastaasi, antitrüpsiini) geeni mutatsioonid; ... PI*S (p.E288V) – kliiniliselt oluline vaid olulise AAT languse ...
    elmy.ee/public/files/T.Kahre - Geneetilised uuringud sise...
  • Type II- 95%
    Gene name SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT ... CK2 (0.555) Polymorphism (dbSNP:rs17655) 8483504 OR5I1 Q13606 F76S 75 VAR_024101 ...
    nih.go.kr/phosphovariant/html/family_whole/TypeII-_95.txt
  • Real time PCR detection of the PI*Z and PI*S mutations ...
    Mutations in the SERPINA1 gene can result in both early onset chronic ... glutamic acid to valine substitution at amino acid 288 (E288V; rs17580) [13, 14] ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2780033

Other in silico analyses
 

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

Edit history
 

Gene search

"GENE" or "GENE A123C":

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