ABCA4 G863A - GET-Evidence

Curation:
Currentness:

ABCA4 G863A

(ABCA4 Gly863Ala)


Short summary

Various publications report this variant causes Stargardt Disease in a recessive manner, when combined with another more severe variant. Stargardt disease causes progressive vision loss and blindness.

Variant evidence
Computational 1

Disease causing gene.

See Allikmets R et al. 1997 (9054934).

Functional

See unpublished research (below).

Case/Control 4

Numerous reports in literature

See Allikmets R et al. 1997 (9054934), Maugeri A et al. 1999 (10090887), Suárez T et al. 2002 (11919200), Maugeri A et al. 2002 (11973624), Kitiratschky VB et al. 2008 (18285826).

Familial 4

Numerous reports in literature

See Allikmets R et al. 1997 (9054934), Maugeri A et al. 1999 (10090887), Suárez T et al. 2002 (11919200), Maugeri A et al. 2002 (11973624), Kitiratschky VB et al. 2008 (18285826).

 
Clinical importance
Severity 4

Severe (but not total) vision loss

Treatability 2

Uncurable, but symptoms are alleviated by sunglasses and magnifiers.

See unpublished research (below).

Penetrance 5

Stargardt disease is generally 100% penetrant (mendelian 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

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Stargardt Disease, Autosomal Recessive
3 45 0 50 0.1137

 

Allele frequency

  • G @ chr1:94517254: 0.5% (53/10758) in EVS
  • Frequency shown in summary reports: 0.5% (53/10758)

Publications
 

Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 Mar;15(3):236-46. Erratum in: Nat Genet. 1997 Sep;17(1):122. PubMed PMID: 9054934.

This variant was identified in three out of 48 families with Stargardt macular dystrophy (one is reported as compound heterozygous, it is unclear what the zygosity is in the other two families). It was not see in 50 control individuals (100 control chromosomes). p = 0.113. Pedigrees are not provided for the reported families and so it is unclear what the LOD score would be.

Cases/controls case+ case– control+ control– p-value odds ratio
Stargardt Disease, Autosomal Recessive
3 45 0 50 0.1137

 

Maugeri A, van Driel MA, van de Pol DJ, Klevering BJ, van Haren FJ, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Dahl N, Brunner HG, Deutman AF, Hoyng CB, Cremers FP. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet. 1999 Apr;64(4):1024-35. PubMed PMID: 10090887; PubMed Central PMCID: PMC1377826.

 

Suárez T, Biswas SB, Biswas EE. Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration. J Biol Chem. 2002 Jun 14;277(24):21759-67. Epub 2002 Mar 27. PubMed PMID: 11919200.

 

Maugeri A, Flothmann K, Hemmrich N, Ingvast S, Jorge P, Paloma E, Patel R, Rozet JM, Tammur J, Testa F, Balcells S, Bird AC, Brunner HG, Hoyng CB, Metspalu A, Simonelli F, Allikmets R, Bhattacharya SS, D'Urso M, Gonzàlez-Duarte R, Kaplan J, te Meerman GJ, Santos R, Schwartz M, Van Camp G, Wadelius C, Weber BH, Cremers FP. The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe. Eur J Hum Genet. 2002 Mar;10(3):197-203. PubMed PMID: 11973624.

 

Kitiratschky VB, Grau T, Bernd A, Zrenner E, Jägle H, Renner AB, Kellner U, Rudolph G, Jacobson SG, Cideciyan AV, Schaich S, Kohl S, Wissinger B. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. Eur J Hum Genet. 2008 Jul;16(7):812-9. doi: 10.1038/ejhg.2008.23. Epub 2008 Feb 20. PubMed PMID: 18285826; PubMed Central PMCID: PMC2579899.

 

Genomes
 

 

 

Other external references
 

    dbSNP
  • rs76157638
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the ABCA4 gene
    Age-related macular degeneration
    ABCA4-Related Retinitis Pigmentosa
    ABCA4-Related Stargardt Disease 1
    Age-Related Macular Degeneration 2
    Cone-Rod Dystrophy, Type 3
    Retinitis Pigmentosa, Autosomal Recessive
    Stargardt Disease, Autosomal Recessive
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ABCA4
    PolyPhen-2
  • Score: 0.991 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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