Submissions for variant NM_003977.4(AIP):c.166C>T (p.Arg56Cys)

gnomAD frequency: 0.00001  dbSNP: rs267606538

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001102833	SCV001259525	uncertain significance	Somatotroph adenoma	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001326205	SCV001517226	uncertain significance	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 56 of the AIP protein (p.Arg56Cys). This variant is present in population databases (rs267606538, gnomAD 0.007%). This missense change has been observed in individual(s) with pituitary macroadenoma (PMID: 21753072). ClinVar contains an entry for this variant (Variation ID: 877266). 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 not expected to disrupt AIP protein function with a negative predictive value of 80%. 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	RCV001326205	SCV002005065	uncertain significance	not provided	2024-02-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23371967, 21753072, 37711900, 37956455)
Ambry Genetics	RCV002402499	SCV002706122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The p.R56C variant (also known as c.166C>T), located in coding exon 2 of the AIP gene, results from a C to T substitution at nucleotide position 166. The arginine at codon 56 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in an individual diagnosed with a prolactinoma (Tichomirowa MA et al. Eur J Endocrinol, 2011 Oct;165:509-15). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.