ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.974G>A (p.Arg325Gln)

gnomAD frequency: 0.00011  dbSNP: rs754619109
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001019700 SCV001181091 likely benign Hereditary cancer-predisposing syndrome 2022-02-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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 RCV001203294 SCV001374451 uncertain significance not provided 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 325 of the AIP protein (p.Arg325Gln). This variant is present in population databases (rs754619109, gnomAD 0.03%). This missense change has been observed in individual(s) with AIP-related conditions (PMID: 22319033, 24078436). ClinVar contains an entry for this variant (Variation ID: 823449). 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%. Experimental studies have shown that this missense change does not substantially affect AIP function (PMID: 27253664, 29632148, 34588620). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003153889 SCV003843051 uncertain significance Somatotroph adenoma 2023-02-22 criteria provided, single submitter clinical testing The AIP c.974G>A (p.Arg325Gln) missense change has a maximum subpopulation frequency of 0.031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been observed in individuals with pituitary adenomas (PMID: 22319033, 23371967, 24078436, 29455389). One individual also harbored a nonsense variant in AIP (PMID: 29455389). The variant segregated with disease in a parent and child with AIP-related conditions and the tumor of one individual showed loss of heterozygosity (PMID: 24078436). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies suggest that this variant is benign (PMID: 29632148, 34588620). 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. 
Baylor Genetics RCV003153889 SCV004193539 uncertain significance Somatotroph adenoma 2023-09-24 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.