ClinVar Genomic variation as it relates to human health

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 27 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Observed in multiple families with Familial Isolated Pituitary Adenoma (FIPA) and in individuals with pituitary adenomas, acromegaly, and gigantism (Vierimaa et al., 2006; Daly et al., 2007; Tichomirowa et al., 2011; Niyazoglu et al., 2014; Marques et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Described as a pathogenic founder variant in Northern Ireland and Italy; however, it may also represent a mutational hot spot (Occhi et al., 2010; Chahal et al., 2011; Ramirez-Renteria et al., 2016; Radian et al., 2017); Published functional studies demonstrate increased cell proliferation, abolished interaction with PDE4A5, and reduced protein half-life (Leontiou et al., 2008; Hernndez-Ramrez et al., 2016); This variant is associated with the following publications: (PMID: 18381572, 27650164, 21208107, 33010004, 27033541, 30941100, 27253664, 30223298, 5320367, 21753072, 12638720, 17360484, 17244780, 16728643, 23743763, 20354355, 23321498, 23371967)

This sequence change creates a premature translational stop signal (p.Arg304*) in the AIP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the AIP protein. This variant is present in population databases (rs104894195, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with pituitary adenomas and pituitary adenomas and acromegaly (PMID: 16728643, 18381572, 20354355, 21208107, 23321498, 23743763, 27033541, 27650164). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4888). For these reasons, this variant has been classified as Pathogenic.

The AIP c.910C>T (p.Arg304Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg304Ter variant has been reported in at least four studies and is found in over 100 probands including at least two in a homozygous state and the rest in a heterozygous state (Occhi et al. 2010; Chahal et al. 2011; Beckers et al. 2013; Hernandez-Ramirez et al. 2015). The majority of probands exhibited familial isolated pituitary adenomas (FIPA), though some probands were found with sporadic pituitary adenomas. Individuals that carried the p.Arg304Ter variant without FIPA were found to exhibit other phenotypes including breast cancer, glioma, osteosarcoma, and neuroendocrine tumor of the colon (Hernandez-Ramirez et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000024 in the European (Non-Finnish) population of the Genome Aggregation Database. Over-expression of the p.Arg304Ter variant AIP protein in HEK293 cells demonstrated that the variant protein has a significantly reduced half-life of 5.9 hours compared to wildtype at 48 hours, and that this could be rescued by proteasomal inhibition (Hernandez-Ramirez et al. 2016). Based on the collective evidence and application of the ACMG criteria, the c.910C>T (p.Arg304Ter) variant is classified as pathogenic for familial isolated pituitary adenomas.

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 (Ramírez-Rentería 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.