Submissions for variant NM_003977.4(AIP):c.308A>G (p.Lys103Arg)

dbSNP: rs267606548

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001018537	SCV001179789	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-18	criteria provided, single submitter	clinical testing	The p.K103R variant (also known as c.308A>G), located in coding exon 3 of the AIP gene, results from an A to G substitution at nucleotide position 308. The lysine at codon 103 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Isolated Pituitary Adenomas (FIPA) (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60; Stratakis CA et al. Clin. Genet. 2010 Nov;78:457-63; Guaraldi F et al. Clin Transl Sci. 2011 Feb;4:55-62; Beckers A et al. Endocr. Rev. 2013 Apr;34:239-77; Dinesen PT et al. Endocrinol Diabetes Metab Case Rep. 2015 Jan;2015:140105). Further, functional analysis using a yeast two-hybrid quantitative b-galactosidase assay assessed the interaction of AIP with PDE4A5, an AIP binding protein, and found that this alteration results in b-galactosidase assay activity values more than fivefold different from wild type suggesting that it leads to a complete loss of PDE4A5–AIP binding (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). However another functional analysis using protein expression of the PDE4A5 rat homologue PDE4A4, suggests the p.K103R alteration has no clear inhibitory effect (Bolger GB et al. Endocr. Relat. Cancer, 2016 May;23:419-31). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001214294	SCV001385969	uncertain significance	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 103 of the AIP protein (p.Lys103Arg). This variant is present in population databases (rs267606548, gnomAD 0.0009%). This missense change has been observed in individual(s) with ACTH-secreting microadenoma (PMID: 20507346). ClinVar contains an entry for this variant (Variation ID: 41174). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AIP function (PMID: 20506337, 28255869). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001214294	SCV001811776	uncertain significance	not provided	2019-07-11	criteria provided, single submitter	clinical testing	Published functional studies are conflicting (Igreja 2010, Bolger 2016, Formosa 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30764022, 21348957, 21512261, 23371967, 20457215, 25614825, 27267386, 28255869, 20507346, 20506337)
GeneReviews	RCV000034073	SCV000058003	not provided	Somatotroph adenoma		no assertion provided	literature only