AIP R304Q - GET-Evidence

Curation:
Currentness:

AIP R304Q

(AIP Arg304Gln)


Short summary

Proposed to cause predisposition to pituitary adenomas, seen in a single Cushing’s syndrome case. Many individuals have pituitary adenomas (about one in five), very few go on to cause hormonal dysregulation. The single case reported for this variant lacked statistical significance.

Variant evidence
Computational

Predicted to be benign by Polyphen 2

Functional -
Case/Control

Reported observation not statistically significant

See Georgitsi M et al. 2007 (17360484).

Familial -
 
Clinical importance
Severity 1

Proposed to cause increased risk of pituitary adenomas. These are quite common, but rarely can form active tumors resulting in hormonal disregulation like Cushing’s syndrome.

See Georgitsi M et al. 2007 (17360484).

Treatability
Penetrance 5

AIP mutations reported as a high penetrance cause of pituitary adenomas

See Georgitsi M et al. 2007 (17360484).

 

Impact

Low clinical importance, Uncertain pathogenic

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

Inheritance pattern

dominant

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr11:67258382: 0.1% (6/10744) in EVS
  • Frequency shown in summary reports: 0.1% (6/10744)

Publications
 

Georgitsi M, Raitila A, Karhu A, Tuppurainen K, Mäkinen MJ, Vierimaa O, Paschke R, Saeger W, van der Luijt RB, Sane T, Robledo M, De Menis E, Weil RJ, Wasik A, Zielinski G, Lucewicz O, Lubinski J, Launonen V, Vahteristo P, Aaltonen LA. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4101-5. Epub 2007 Feb 28. PubMed PMID: 17360484; PubMed Central PMCID: PMC1820715.

Sequencing AIP in 460 pituitary adenoma patients and patients from families with MEN1 features (but not MEN1 mutations). This was seen in one of 122 pituitary adenoma patients from Poland.

The authors also note seeing this variant in an Italian patient with acromegaly — this is noted as unpublished data, and the total number of patients screened is not mentioned. The authors also state the variant was not seen in healthy controls. Controls are elsewhere described as 110 Caucasian from CEPH, 288 UK Caucasians, 209 Finns, 90 Germans, and 52 Italians (749 total European control individuals).

For case/control significance evaluation, we consider all patients screened by this paper as part of cases. case+: 1, case-: 459, control+: 0, control-: 749. There is no statistically significant enrichment of the variant in cases.

Genomes
 

Other external references
 

    dbSNP
  • rs104894190
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.417 (possibly damaging)
    Web search results (13 hits -- see all)
  • The Role of the Aryl Hydrocarbon Receptor-Interacting Protein ...
    In sporadic pituitary adenomas, however, AIP is expressed in all tumor types. ... of AIP mutations is consistent with a tumor-suppressor role for AIP and its ...
    jcem.endojournals.org/cgi/content/full/93/6/2390
  • Geographical cluster of familial isolated pituitary adenoma ...
    Mutations in the co-chaperone molecule AIP account for a predisposition to pituitary ... other is an aminoacid change (c.911G>A,p.R304Q). As this locus is a mutational hotspot, ...
    www.endocrine-abstracts.org/ea/0021/ea0021OC2.4.htm
  • Characteristics of Familial Isolated Pituitary Adenomas ...
    Familial Isolated Pituitary Adenomas: Familial isolated pituitary adenomas are an increasingly recognized condition. This article reviews FIPA clinical ...
    www.medscape.com/viewarticle/565829_3
  • Characteristics of Familial Isolated Pituitary Adenomas ...
    Expert Commentary: Familial isolated pituitary adenomas are an increasingly recognized ... of patients in FIPA families with AIP mutations is an area of particular importance ...
    www.medscape.com/viewarticle/565829_4
  • Type II- 97%
    ... HMBS P08397 R167W 165 VAR_003652 PKC (0.916) AIP 1496994 1301948 9225970 10602775 NLRP3 Q96P20 A352V 343 ... (dbSNP:rs28763886) ALDOB P05062 R304Q 309 VAR_020828 AKT (0.554) HFI, ...
    nih.go.kr/phosphovariant/html/family_whole/TypeII-_97.txt
  • Susceptibility to pituitary neoplasia related to MEN-1 ...
    AIP gene germline mutations detected and predicted effect ... (5,38) R304Q. ex 6. ms (37) fs, frame shift; ns, nonsense mutation; ms, missense mutation; ...
    hmg.oxfordjournals.org/cgi/content/full/16/R1/R73/DDM036TB2
  • OMIM: 605555
    The lack of AIP expression in the liver led Kuzhandaivelu et al. (1996) to hypothesize that this may ... 6 of the AIP gene, resulting in an arg304-to-gln (R304Q) substitution. ...
    www.genome.jp/dbget-bin/www_bget?omim+605555
  • Hum. Mol. Genet. -- Karhu and Aaltonen 16 (1): R73 Figure ...
    Table 2. AIP gene germline mutations detected and predicted effect. Mutation. Exon ... R304Q. ex 6. ms (37) fs, frame shift; ns, nonsense mutation; ms, ...
    hmg.oxfordjournals.org/cgi/content-nw/full/.../R73/DDM036TB2

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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