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

gnomAD frequency: 0.00011  dbSNP: rs754619109

Total submissions: 6

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.
Labcorp Genetics (formerly Invitae), Labcorp	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
GeneDx	RCV001203294	SCV005079137	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24789813, 23300914, 29632148, 29455389, 23371967, 27253664, 22319033, 34588620, 24078436)
PreventionGenetics, part of Exact Sciences	RCV004749585	SCV005351825	uncertain significance	AIP-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The AIP c.974G>A variant is predicted to result in the amino acid substitution p.Arg325Gln. This variant was reported in individuals with pituitary adenomas (Cazabat et al. 2012. PubMed ID: 22319033; García-Arnés et al. 2013. PubMed ID: 24078436; Hernández-Ramírez et al. 2016. PubMed ID: 27253664). A familial case study revealed this variant to be present in an affected mother, affected son, and asymptomatic son (García-Arnés et al. 2013. PubMed ID: 24078436). Biochemical studies of the p.Arg325Gln variant demonstrated a similar half-life to wild-type protein, suggesting protein stability is conserved (Hernández-Ramírez et al. 2016. PubMed ID: 27253664). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/823449/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.