Submissions for variant NM_003977.4(AIP):c.911G>A (p.Arg304Gln)

gnomAD frequency: 0.00115  dbSNP: rs104894190

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000508590	SCV000373587	likely benign	Somatotroph adenoma	2017-07-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000766368	SCV000512006	uncertain significance	not provided	2016-07-21	criteria provided, single submitter	clinical testing	The R304Q variant in the AIP gene has been reported in the literature in several patients with familial isolated pituitary adenoma, sporadic pituitary adenoma, acromegaly, and/or hyperparathyroidism (Georgitsi et al., 2007; Igreja et al., 2010; Occhi et al., 2010; Tichomirowa et al., 2011; Cazabat et al., 2012; Cuny et al., 2013; Pardi et al., 2013; Preda et al., 2014; Schofl et al., 2014). This variant is located in the aryl hydrocarbon receptor (AHR) binding region and has been hypothesized to impact AIP and AHR interactions (Georgitisi et al., 2007). However, AIP also interacts with PDE4A5 and in vitro AIP-PDE4A5 functional assays suggest that the R304Q variant only has a minimal effect on AIP-PDE4A5 binding (Igreja et al., 2010). Although the R304Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, this variant has been observed in 3/44 (6.8%) of unaffected centenarian patients of Ashkenazi Jewish ancestry (Freudenberg-Hua et al., 2014). The R304Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the R304Q variant is damaging to the protein structure/function. Therefore, we interpret R304Q as a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000439236	SCV000538256	uncertain significance	not specified	2018-09-25	criteria provided, single submitter	clinical testing	The p.Arg304Gln variant in AIP has been reported in >10 individuals with pituita ry adenoma and segregated with disease in two affected members across two famili es (Georgitsi 2007, Igreja 2010, Occhi 2010, Tichomirowa 2011, Cazabat 2012, Cun y 2013, Pardi 2013, Preda 2014, Schofl 2014, Arajuo 2017). This variant has also been identified in multiple individuals without pituitary lesions (Tichomirowa 2011, Freudenberg-Hua 2014, Pardi 2013) and in 2.07% (208/10074) of Ashkenazi Je wish chromosomes, including 2 homozygous individuals, by gnomAD (http://gnomad.b roadinstitute.org). However, this frequency does not rule out a pathogenic role due to the prevalence of pituitary adenoma in the general population (~11% on au topsy; Molitch 2008) and the reduced penetrance of pituitary adenoma in individu als carrying pathogenic AIP variants (15-30%; Korbonits 2018). In vitro function al studies suggest that the p.Arg304Gln variant does not have a strong impact on protein function (Georgitisi 2007, Igreja 2010, Morgan 2012); however these typ es of assays may not accurately represent biological function. Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. Finally, this variant is present in ClinVar with conflicting interpretations of pathogenicity (Variation ID# 4893). In summary, t he clinical significance of the p.Arg304Gln variant is uncertain. ACMG/AMP Crit eria applied: PS4_Moderate, BS3_Supporting.
Ambry Genetics	RCV000571906	SCV000664979	likely benign	Hereditary cancer-predisposing syndrome	2020-02-20	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.
Invitae	RCV000766368	SCV001050682	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000508590	SCV001138359	uncertain significance	Somatotroph adenoma	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000766368	SCV001441059	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000766368	SCV002009985	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000508590	SCV002525988	uncertain significance	Somatotroph adenoma	2023-06-22	criteria provided, single submitter	clinical testing	The AIP c.911G>A (p.Arg304Gln) missense change has a maximum subpopulation frequency of 0.14% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A ß-galactosidase activity assay in yeast showed a mild reduction of ß-galactosidase activity compared to wildtype (PMID: 20506337). This variant has been reported in individuals with pituitary adenoma (PMID: 17360484, 17609395, 18381572, 19366855, 20506337). 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.
Sema4, Sema4	RCV000571906	SCV002535462	likely benign	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000766368	SCV004137040	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	AIP: BP4
OMIM	RCV000508590	SCV000025348	pathogenic	Somatotroph adenoma	2007-03-06	flagged submission	literature only
GeneReviews	RCV000005171	SCV000055843	not provided	Pituitary dependent hypercortisolism		no assertion provided	literature only
Aziz Sancar Institute of Experimental Medicine, Istanbul University	RCV000508590	SCV000693856	pathogenic	Somatotroph adenoma	2018-03-09	flagged submission	research	a variant already in ClinVar database associated with clinical findings in a Turkish patient
Aziz Sancar Institute of Experimental Medicine, Istanbul University	RCV000735427	SCV000693857	drug response	Dopamine agonists response	2018-03-09	no assertion criteria provided	research	a variant already in ClinVar database associated with drug response in a Turkish patient