Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001379496 | SCV001577308 | likely pathogenic | not provided | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 238 of the AIP protein (p.Cys238Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pituitary adenoma (PMID: 18381572). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41197). 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 expected to disrupt AIP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AIP function (PMID: 18381572, 20506337, 23300914, 27253664, 29632148, 34588620). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV004018729 | SCV005021301 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | The p.C238Y variant (also known as c.713G>A), located in coding exon 5 of the AIP gene, results from a G to A substitution at nucleotide position 713. The cysteine at codon 238 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in 3 siblings with pituitary adenomas leading to acromegaly (Leontiou CA et al. J Clin Endocrinol Metab, 2008 Jun;93:2390-401). In multiple functional studies, the p.C238Y variant demonstrated reduced ability to inhibit cellular proliferation compared to wild-type, impaired AIP-PDE445 interaction, and was show to have a reduced half-life compared to wild-type (Leontiou CA et al. J Clin Endocrinol Metab, 2008 Jun;93:2390-401; Igreja S et al. Hum Mutat, 2010 Aug;31:950-60; Hernández-Ramírez LC et al. J Clin Endocrinol Metab, 2016 Aug;101:3144-54; Garcia-Rendueles AR et al. Oncogene, 2021 Nov;40:6354-6368). Based on internal structural analysis, p.C238Y is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV000034096 | SCV000058026 | not provided | Somatotroph adenoma | no assertion provided | literature only |