AIPL1 T114I - GET-Evidence

Curation:
Currentness:

AIPL1 T114I

(AIPL1 Thr114Ile)


Short summary

This variant is reported causative for Leber Congenital Amaurosis IV.

Variant evidence
Computational 2

Conserved in Rat/AIP homologue. Gene is associated with disease.

See Sohocki MM et al. 2000 (10873396), Dharmaraj S et al. 2004 (15249368).

Functional
Case/Control

Adding 1000 genomes as controls, where this variant is 5.4%, renders the evidence for this not significant.

See Dharmaraj S et al. 2004 (15249368).

Familial
 
Clinical importance
Severity 4

Causes blindness

Treatability 2

Gene therapy is being tried

Penetrance 5

Proposed effect is highly penetrant

 

Impact

High clinical importance, Uncertain pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

All three (or two) cases are compound heterozygous for P376S.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
AIPL1-Related Leber Congenital Amaurosis
- - 6 106 - -
Leber Congenital Amaurosis
- - 6 106 - -

 

Total cases/controls case+ case– control+ control– p-value odds ratio
AIPL1-Related Leber Congenital Amaurosis
2 24 6 311 0.1166 4.319
Leber Congenital Amaurosis
2 301 6 311 0.2869 0.344

 

Allele frequency

  • A @ chr17:6331762: 2.0% (216/10758) in EVS
  • A @ chr17:6272485: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 2.0% (216/10758)

Publications
 

Sohocki MM, Perrault I, Leroy BP, Payne AM, Dharmaraj S, Bhattacharya SS, Kaplan J, Maumenee IH, Koenekoop R, Meire FM, Birch DG, Heckenlively JR, Daiger SP. Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol Genet Metab. 2000 Jun;70(2):142-50. PubMed PMID: 10873396.

In a screen of 512 individuals with inherited retinal degenerative disease, this variant (aka T124I) was found as a compound heterozygote with P376S in an African American child. Controls are not reported for this variant. This variant is conserved in rat and a conservative mutation occurs in the homologue AIP.

Dharmaraj S, Leroy BP, Sohocki MM, Koenekoop RK, Perrault I, Anwar K, Khaliq S, Devi RS, Birch DG, De Pool E, Izquierdo N, Van Maldergem L, Ismail M, Payne AM, Holder GE, Bhattacharya SS, Bird AC, Kaplan J, Maumenee IH. The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol. 2004 Jul;122(7):1029-37. PubMed PMID: 15249368.

In a screen of 303 individuals with Leber congenital amaurosis, this variant was seen as a compound heterozygote in two individuals together with P376S (one American and one French). The author overlap makes it likely that the patient in Sohocki et al. is the same patient. It was not seen in 205 controls. The French patient had severe pigmentary retinopathy, while the 8yo American had night blindness, was 20/400 with severe maculopathy, mild optic nerve pallor and moderate pigmentary retinopathy.

Cases/controls case+ case– control+ control– p-value odds ratio
AIPL1-Related Leber Congenital Amaurosis
2 24 0 205 0.0122
Leber Congenital Amaurosis
2 301 0 205 0.5177

 

Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Schwartz SB, Roman AJ, Stone EM. Leber congenital amaurosis caused by an RPGRIP1 mutation shows treatment potential. Ophthalmology. 2007 May;114(5):895-8. Epub 2007 Feb 16. PubMed PMID: 17306875.

 

Genomes
 

GS18517 - var-GS18517-1100-36-ASM
het A @ chr17:6272486

 

NA18517

This genome harbors both mutations found in these two compound heterozygotes. The publications do not explicitly state that the variants are in trans.

Other external references
 

    dbSNP
  • rs8069375
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the AIPL1 gene
    Leber Congenital Amaurosis
    AIPL1-Related Leber Congenital Amaurosis
    AIPL1-Related Retinitis Pigmentosa
    Retinitis Pigmentosa, Autosomal Dominant
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/AIPL1
    PolyPhen-2
  • Score: 0.191 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in