ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.805_825dup (p.Phe269_His275dup) (rs267606578)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001027111 SCV001189617 pathogenic Hereditary cancer-predisposing syndrome 2019-10-17 criteria provided, single submitter clinical testing The c.805_825dup21 pathogenic mutation (also known as p.F269_H275dup), located in coding exon 6 of the AIP gene, results from an in-frame duplication of 21 nucleotides at nucleotide positions 805 to 825. This results in the duplication of 7 extra residues (FKRGKAH) between codons 269 and 275. This duplication has been reported in multiple individuals with familial isolated pituitary adenomas (FIPA) resulting in gigantism and/or acromegaly, although some carriers in these families remained unaffected (Leontiou CA et al. J. Clin. Endocrinol. Metab. 2008 Jun;93(6):2390-401; Igreja S. et al. Hum. Mutat. 2010 Aug;31(8):950-60; Salvatori R. et al. Eur. J. Endocrinol. ​2017 Sep;177(3):257-266; Cazabat L et al. J. Clin Endocrinol. Metab. 2012 Apr;97(4):E663-70). One affected individual also developed a GIST (Hernandez-Ramire LC et al. J. Clin. Endocrinol. Metab. 2015 Sep;100(9):E1242-54). Authors of one study proposed replication slipage as the mechanism for this duplication and report this as an English founder mutation due to a shared haplotype around AIP in affected, unrelated individuals (Salvatori R. et al. Eur. J. Endocrinol. ​2017 Sep;177(3):257-266). In addition, co-immunoprecipitation with this AIP mutant and HSP90 showed lack of interaction between these two proteins, resulting in reduced protein stability (Salvatori R. et al. Eur. J. Endocrinol. 2017 Sep;177(3):257-266). Furthermore, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also referred to as c.794_823dup (p.A247_H275ins10) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001386204 SCV001586343 pathogenic not provided 2020-01-31 criteria provided, single submitter clinical testing This variant, c.805_825dup, results in the insertion of 7 amino acid(s) to the AIP protein (p.Phe269_His275dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with pituitary adenoma (PMID: 26186299, 28634279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41208). This variant has been reported to affect AIP protein function (PMID: 28634279). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000034107 SCV000058037 pathologic Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Pathogenic.

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