ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 271 of the AIP protein (p.Arg271Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial and sporadic pituitary adenomas (PMID: 17244780, 19684062, 21753072, 26186299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIP protein function. Experimental studies have shown that this missense change affects AIP function (PMID: 20506337, 27253664). For these reasons, this variant has been classified as Pathogenic.

AIP: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting

The p.R271W variant (also known as c.811C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 811. The arginine at codon 271 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been identified in multiple individuals with a personal and/or family history of pituitary adenomas and segregates with disease in multiple families (De Sousa SMC et al. Eur J Endocrinol, 2017 May;176:635-644; Jennings JE et al. Eur J Endocrinol, 2009 Nov;161:799-804; Daly AF et al. J Clin Endocrinol Metab, 2007 May;92:1891-6; Ambry internal data). This alteration induced severely reduced protein half-life which was a suggested mechanism for tumorigenesis (Hernández-Ramírez LC et al. J Clin Endocrinol Metab, 2016 08;101:3144-54). Based on internal structural analysis, R271W is highly destabilizing to the structure near a region known to interact with several other proteins and disrupts hydrogen bonds which are important to the stability of the TPR domain fold (Morgan RM et al. PLoS One, 2012 Dec;7:e53339; Das AK et al. EMBO J, 1998 Mar;17:1192-9; Bolger GB et al. J Biol Chem, 2003 Aug;278:33351-63; Igreja S et al. Hum Mutat, 2010 Aug;31:950-60). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.