Submissions for variant NM_003977.4(AIP):c.26G>A (p.Arg9Gln)

gnomAD frequency: 0.00037  dbSNP: rs139459091

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561910	SCV000672425	likely benign	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000765005	SCV000896188	uncertain significance	Acroleukopathy, symmetric; Pituitary dependent hypercortisolism; Somatotroph adenoma	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001054806	SCV001219159	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001054806	SCV001747603	uncertain significance	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001054806	SCV002009993	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561910	SCV002535435	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
GeneDx	RCV001054806	SCV002601483	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pituitary adenomas and/or multiple neuroendocrine neoplasia in published literature (Cazabat et al., 2012; Oriola et al., 2013; Lecoq et al., 2016; Pardi et al., 2017; Martinez de LaPiscina et al., 2021); Published functional studies demonstrate partially reduced protein stability, cellular proliferation and cAMP-directed expression (Formosa et al., 2017); This variant is associated with the following publications: (PMID: 22319033, 29036195, 23038625, 30941100, 26792934, 34313605, 25614825, 29308445, 28255869)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001764674	SCV003842999	uncertain significance	Somatotroph adenoma	2023-01-19	criteria provided, single submitter	clinical testing	The AIP c.26G>A (p.Arg9Gln) missense change has a maximum subpopulation frequency of 0.079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with prolactin-secreting pituitary adenomas and hormonal dysfunction (PMID: 22319033, 34313605), an individual with a pituitary macroadenoma of unknown type (PMID: 23038625), and an individual with multiglandular familial primary hyperparathyroidism and a mixed prolactin- and GH-secreting pituitary adenoma (PMID: 29036195). The in silico tool REVEL predicts a benign effect on protein function, and in vitro functional studies demonstrated that this variant impacts the cAMP inhibitory ability of the wild-type AIP protein and may decrease the half-life of the protein (PMID: 28255869). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001054806	SCV001550414	uncertain significance	not provided		no assertion criteria provided	clinical testing	The AIP p.Arg9Gln variant was identified in dbSNP (ID: rs139459091) as “With Uncertain significance allele”, ClinVar (Uncertain Significance, Ambry Genetics), the LOVD 3.0 database (as Likely Pathogenic), the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 4 of 8586 European American and 0 of 4400 African American alleles. The variant was identified in gnomAD (Feb 27, 2017) control databases in 69 of 282814 chromosomes at a frequency of 0.000244. It was observed in the following populations: Latino in 28 of 35436 chromosomes (freq: 0.00079), Other in 5 of 7226 chromosomes (freq: 0.000692), European (non-Finnish) in 34 of 129136 chromosomes (freq: 0.000263), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and African in 1 of 24962 chromosomes (freq: 0.00004); it was not observed in the East Asian, European (Finnish) and South Asian populations. The AIP p.Arg9Gln variant was identified in a 21 year-old female with Acromegaly and a pituitary macroadenoma, but was not identified in the controls (Oriola_2012_PMID: 23038625). This patient presented with complete resistance to somatostatin analogues and had no family history of pituitary adenomas or other endocrine tumors. Similarly, the variant was identified in a 14 year-old female with PRL-secreting pituitary macroadenoma (diameter between 10 and 29 mm) originally presenting with primary amenorrhea and a 39 year-old female with ACTH-secreting microadenoma sized (diameter less than 10 mm) originally presenting with Cushing syndrome (Cazabat_2012_PMID: 22319033). Both of these patients had no family history of pituitary adenomas. In a study by Pardi et al., the p.Arg9Gln variant was identified in two Italian patients with sporadic cases of multiple endocrine neoplasia type 1 (no family history of multiple endocrine neoplasia–related manifestations), but was not identified in healthy controls (Pardi_2017_PMID: 29036195). The p.Arg9 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD and BLOSUM) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE and GeneSplicer) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.