SIAE M89V - GET-Evidence

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SIAE M89V

(SIAE Met89Val)


You are viewing an old version of this page that was saved on November 17, 2010 at 10:59am by Madeleine Ball.

Short summary

This variant, which has a 3.4% allele frequency in 1000 genomes data, is reported to be associated with autoimmune disease when homozygous. The statistical significance of the findings is unclear. Assuming it is pathogenic, we estimate that the relative risk of autoimmune disease in homozygous individuals is around 4x (8% risk vs. an average of 2% risk).

Variant evidence
Computational 1

Polyphen predicts “possibly damaging”. Surolia et al. find other variants in this gene associated with autoimmune disease.

Functional 2

Surolia et al. report that the protein product with this variant is catalytically active but is not secreted. This finding was reproduced in a pulse-chase experiment with 35S-methionine.

Case/Control 1

Surolia et al., see below.

See unpublished research (below).

Familial -
 
Clinical importance
Severity 2

Not expected to be fully penetrant.

Treatability 4

Autoimmune diseases can be treated with immunosuppressive drugs.

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

Surolia, I. et al. Nature advance online publication doi:10.1038/nature09115 (2010). — This paper implicates this polymorphism as potentially contributing to autoimmune diseases when homozygous. The variant was seen homozygously in 8 out of 923 cases and 0 out of 648 controls. Using two-tailed Fisher’s Exact, this is p = 0.024. However, because there are several other polymorphisms, multiple hypotheses were implicitly being tested and so we give this a case/control significance of 1 point (0.1 < p < 0.05). The overall allele frequency of the variant in controls is 0.049, they list four other variants with allele frequencies > 0.025.

They report that the protein product with this variant is catalytically active but is not secreted. This finding was reproduced in a pulse-chase experiment with 35S-methionine.

This data suggests homozygosity for this variant explains ~1% of autoimmune cases. An allele frequency of 0.049 implies that .24% of people are homozygous for this variant. Assuming an incidence of autoimmune disease in 1 out of 50 people, 0.02% of people would be expected to have autoimmune disease that might be attributed to this variant — this puts an estimate of penetrance for autoimmune disease in the homozygous individuals at ~8% (.02 / .24), approximately fourfold relative risk.

Allele frequency

  • C @ chr11:124530664: 4.0% (431/10758) in EVS
  • C @ chr11:124035873: 5.5% (7/128) in GET-Evidence
  • Frequency shown in summary reports: 4.0% (431/10758)

Publications
 

Added in this revision:

Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature. 2010 Jul 8;466(7303):243-7. Epub 2010 Jun 16. PubMed PMID: 20555325; PubMed Central PMCID: PMC2900412.

 

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr11:124530664

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr11:124530664

 

Other external references
 

    dbSNP
  • rs78778622
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.015 (benign)

Other in silico analyses
 

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

Edit history
 

Gene search

"GENE" or "GENE A123C":

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