ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.910C>T (p.Arg304Ter) (rs104894195)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001018873 SCV001180162 pathogenic Hereditary cancer-predisposing syndrome 2019-11-20 criteria provided, single submitter clinical testing The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration has been well described in numerous individuals with personal and/or family history consistent with AIP-Related Familial Isolated Pituitary Adenomas (Vierimaa O et al. Science, 2006 May;312:1228-30; Georgitsi M et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Mar;104:4101-5; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Niyazoglu M et al. Pituitary, 2014 Jun;17:220-6; Radian S et al. Hum. Mutat., 2017 01;38:78-85). Haplotype studies have concluded this alteration to be both an Italian and Irish founder mutation (Occhi G et al. J. Endocrinol. Invest., 2010 Dec;33:800-5; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50); however, given the presence of this alteration in other populations, including Turkish and Mexican, who do not share a common haplotype, it has been suggested that this alteration may arise from independent, recurring mutational events<span style="font-family:arial,sans-serif; font-size:13.3333px"> (Ram&iacute;rez-Renter&iacute;a C et al. Endocrine, 2016 Aug;53:402-11). Functional analysis of the effect of this alteration on cell proliferation has shown reduced ability to block cell proliferation compared with wild-type AIP (Leontiou CA et al. J. Clin. Endocrinol. Metab., 2008 Jun;93:2390-401). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of AIP, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 27 amino acids of the protein. While the exact functional impact of these removed amino acids is unknown at this time, the final carboxy-terminal amino acids are presumed necessary for interactions of AIP with heat shock protein 90 (hsp90) and the aryl hydrocarbon receptor (AhR) (Petrulis JR et al. Chem. Biol. Interact., 2002 Sep;141:25-40; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6). As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001213277 SCV001384903 pathogenic not provided 2020-09-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the AIP gene (p.Arg304*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acids of the AIP protein. This variant is present in population databases (rs104894195, ExAC 0.003%). This variant has been reported to segregate with pituitary adenomas in several families (PMID: 16728643, 27650164, 20354355, 21208107, 23743763, 18381572) and has been reported in multiple individuals with pituitary adenomas and acromegaly (PMID: 27033541, 23321498). ClinVar contains an entry for this variant (Variation ID: 4888). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001213277 SCV001500974 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
OMIM RCV000005166 SCV000025343 pathogenic Somatotroph adenoma 2011-01-06 no assertion criteria provided literature only
GeneReviews RCV000005166 SCV000055842 pathologic Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.