BLMH I443V - GET-Evidence

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

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Curation:
Currentness:

BLMH I443V

(BLMH Ile443Val)


Short summary

The exact function of BLMH, a cysteine protease of the papain superfamily, is unknown, but has been associated with increased risk of Alzheimer’s Disease (AD) in non-APOE4 individuals through a homozygous A->G nucleotide exchange. This variant increases the release of the proteolytic fragment, β-amyloid, in amyloid precursor proteins, which is a key event in the pathogenesis of AD. Case control studies studying the 1443V variant reported median prevalence for the A/A + A/G genotypes was 0.86. Increased AD risk with common G/G genotype was seen through higher frequency of the G/G phenotype among AD patients compared with control subjects. Increased risk for AD in individuals homozygous for the G allele confined it to non-APOE4 individuals. Although studies have found contradictory results, the potential important of this variant places it as a novel target for HD therapeutics.

Variant evidence
Computational 2

PolyPhen2: Benign, score 0.000
SIFT: Tolerated 1.00
GVGD: GV 28.68; GD 0.00; Class C0
Variant Effect Predictor (Ensembl):
SIFT=tolerated(1);
PolyPhen=benign(0);
Condel=not_computable_was(-1)
Mutation Tasting Prediction: Polymorphism, P value: 0.999775; protein features (might be) affected (aa 442-444 STRAND gets lost)

Functional 2

Llorca, J., E. Rodriguez-Rodriguez, et al. (2008). “Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer’s disease.” Acta Neurol Scand 117(1): 1-14.

Case/Control -1

Smach, M. A., B. Charfeddine, et al. (2010). “Analysis of association between bleomycin hydrolase and apolipoprotein E polymorphism in Alzheimer’s disease.” Neurol Sci 31(6): 687-691.

Familial
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pathogenic

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

There have been contradictory results in studying BLMH variants in relation to AD. AD is the most common form of dementia and is currently incurable. Most individuals begin showing symptoms after age 60 and 10% of people aged 65-74 have AD. The causes of AD are not fully understood, but genetic factors, including gene variant APOE-4, have shown strong associations with the development of AD. Recently, other variants have been studied and linked with AD, such as BLMH 1442V. Unlike APOE-4, no strong association has been concretely defined in this variant; some studies show degenerative effects of BLMH on the brain while others found protective qualities of the G/G genotype in AD development.

Allele frequency

  • C @ chr17:28576076: 28.5% (3065/10758) in EVS
  • C @ chr17:25600201: 23.4% (30/128) in GET-Evidence
  • Frequency shown in summary reports: 28.5% (3065/10758)

Publications
 

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr17:28576076

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr17:28576076

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het C @ chr17:28576076

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het C @ chr17:28576076

 

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het C @ chr17:28576076

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
hom C @ chr17:28576076

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het C @ chr17:28576076

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het C @ chr17:28576076

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr17:28576076

 

 

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
het C @ chr17:28576076

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het C @ chr17:28576076

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het C @ chr17:28576076

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
hom C @ chr17:28576076

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het C @ chr17:28576076

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het C @ chr17:28576076

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
het C @ chr17:28576076

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
het C @ chr17:28576076

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het C @ chr17:28576076

 

GS10851 - var-GS10851-1100-36-ASM
hom C @ chr17:25600202

 

GS12004 - var-GS12004-1100-36-ASM
het C @ chr17:25600202

 

GS18501 - var-GS18501-1100-36-ASM
het C @ chr17:25600202

 

GS18942 - var-GS18942-1100-36-ASM
het C @ chr17:25600202

 

GS18956 - var-GS18956-1100-36-ASM
hom C @ chr17:25600202

 

GS19017 - var-GS19017-1100-36-ASM
het C @ chr17:25600202

 

GS19026 - var-GS19026-1100-36-ASM
het C @ chr17:25600202

 

GS19239 - var-GS19239-1100-36-ASM
het C @ chr17:25600202

 

GS19240 - var-GS19240-1100-36-ASM
het C @ chr17:25600202

 

GS19648 - var-GS19648-1100-36-ASM
het C @ chr17:25600202

 

GS19649 - var-GS19649-1100-36-ASM
het C @ chr17:25600202

 

GS19670 - var-GS19670-1100-36-ASM
het C @ chr17:25600202

 

GS19700 - var-GS19700-1100-36-ASM
het C @ chr17:25600202

 

GS19701 - var-GS19701-1100-36-ASM
het C @ chr17:25600202

 

GS19703 - var-GS19703-1100-36-ASM
het C @ chr17:25600202

 

GS19735 - var-GS19735-1100-36-ASM
het C @ chr17:25600202

 

GS20502 - var-GS20502-1100-36-ASM
het C @ chr17:25600202

 

NA12878

 

Other external references
 

    dbSNP
  • rs1050565
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = –4
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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