ClinVar Miner

Submissions for variant NM_003977.3(AIP):c.911G>A (p.Arg304Gln) (rs104894190)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571906 SCV000664979 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Aziz Sancar Institute of Experimental Medicine,Istanbul University RCV000508590 SCV000693856 pathogenic Somatotroph adenoma 2018-03-09 no assertion criteria provided 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 agonist response 2018-03-09 no assertion criteria provided research a variant already in ClinVar database associated with drug response in a Turkish patient
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.
GeneReviews RCV000005171 SCV000055843 pathologic Pituitary dependent hypercortisolism 2012-06-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000408430 SCV000373587 likely benign Familial Isolated Pituitary Adenomas 2016-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000439236 SCV000538256 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 individuals with pitutary adenomas, but no LOH was found (Pardi 2013), one patient with acromegaly (Preda 2014), one patient with pituitary adenoma and in the healthy mother (Cuny 2013).No difference in interaction with PDE4A5 in yeast two hybrid assay (Igreja 2010). Fre 0.2% in ExAC.
OMIM RCV000508590 SCV000025348 pathogenic Somatotroph adenoma 2007-03-06 no assertion criteria provided literature only

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