ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.949G>T (p.Asp317Tyr)

dbSNP: rs145025838
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001019413 SCV001180768 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-26 criteria provided, single submitter clinical testing The p.D317Y variant (also known as c.949G>T), located in coding exon 6 of the AIP gene, results from a G to T substitution at nucleotide position 949. The aspartic acid at codon 317 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001212933 SCV001384544 uncertain significance not provided 2023-11-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 317 of the AIP protein (p.Asp317Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AIP-related conditions. ClinVar contains an entry for this variant (Variation ID: 823287). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 RCV001543119 SCV001761633 uncertain significance Familial isolated pituitary adenoma 2021-07-15 criteria provided, single submitter clinical testing The AIP c.949G>T (p.Asp317Tyr) missense change has a maximum subpopulation frequency of 0.00091% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-67258420-G-T). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with familial isolated pituitary adenoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002254716 SCV002525967 uncertain significance Somatotroph adenoma 2022-02-17 criteria provided, single submitter clinical testing The AIP c.949G>T (p.Asp317Tyr) missense change has a maximum subpopulation frequency of 0.00091% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-67258420-G-T). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with familial isolated pituitary adenoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4.
Baylor Genetics RCV002254716 SCV005060250 uncertain significance Somatotroph adenoma 2023-11-09 criteria provided, single submitter clinical testing
GeneDx RCV001212933 SCV005379295 uncertain significance not provided 2023-11-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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