Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001024357 | SCV001186357 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-06-13 | criteria provided, single submitter | clinical testing | The p.R188Q variant (also known as c.563G>A), located in coding exon 4 of the AIP gene, results from a G to A substitution at nucleotide position 563. The arginine at codon 188 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in one individual with sporadic pituitary adenoma (Cazbat et al. J. Clin. Endocrinol. Metab.2012 Apr;97(4):E663-70). In one functional study, this variant demonstrated normal half-life compared to wild-type and did not affect the RET-apoptotic pathway (Garcia-Rendueles AR et al. Oncogene, 2021 Nov;40:6354-6368). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV001062614 | SCV001227428 | uncertain significance | not provided | 2024-05-21 | 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 188 of the AIP protein (p.Arg188Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pituitary adenoma (PMID: 22319033). ClinVar contains an entry for this variant (Variation ID: 825866). 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: 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. |
| Prevention |
RCV003396613 | SCV004104807 | uncertain significance | AIP-related disorder | 2023-01-11 | criteria provided, single submitter | clinical testing | The AIP c.563G>A variant is predicted to result in the amino acid substitution p.Arg188Gln. This variant was reported in at least one individual who presented with pituitary adenoma (Patient 9, Cazabat et al. 2012. PubMed ID: 22319033; Beckers et al. 2013. PubMed ID: 23371967). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/825866). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV003461399 | SCV004195916 | uncertain significance | Somatotroph adenoma | 2023-06-28 | criteria provided, single submitter | clinical testing |