ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.896C>T (p.Ala299Val) (rs148986773)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000034113 SCV000373585 likely benign Somatotroph adenoma 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx RCV001357152 SCV000521287 likely benign not provided 2021-05-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27267386, 28220018, 29074612, 22720333, 27253664, 27535533, 27153395, 20506337, 24423289, 17360484)
Ambry Genetics RCV000571818 SCV000664959 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing The p.A299V variant (also known as c.896C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 896. The alanine at codon 299 is replaced by valine, an amino acid with similar properties. This variant has been identified in patients with hormone-secreting and non-functional pituitary adenomas (Georgitsi M et al. Proc. Natl. Acad. Sci. U.S.A. 2007 Mar;104:4101-5; De Sousa SM et al. Eur. J. Endocrinol. 2017 May;176:635-644; Araujo PB et al. Endocr Connect. 2017 Nov;6:914-925). Additionally, it was seen in an Irish patient with prolactinoma at 30; four other unaffected family members also carried p.A299V, and two carried AIP p.R304* in trans (Williams F et al. J. Clin. Endocrinol. Metab. 2014 Apr;99:1122-31; Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). Two functional studies investigating the interaction between AIP and the PDE4A5 protein showed no clear difference in interaction (Bolger GB et al. Endocr. Relat. Cancer. 2016 May;23:419-31) and binding that was approximately 60% of wild type (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). Additionally, the p.A299V variant displayed shortened half-life in transfected HEK293 cells when compared to wild type protein, but this was not reduced to the levels demonstrated by a known pathogenic variant (Hernández-Ramírez LC et al. J. Clin. Endocrinol. Metab. 2016 Aug;101:3144-54). 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. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001357152 SCV001605607 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing
GeneReviews RCV000034113 SCV000058043 unknown Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357152 SCV001552523 likely benign not provided no assertion criteria provided clinical testing The AIP p.A299V variant was identified in 1 of 72 proband chromosomes (frequency: 0.0139) from endocrine neoplasia-predisposition patients from the Netherlands who were negative for MEN1 mutations (Georgitsi_2007_PMID:17360484). The p.A299V variant was also identified in a family with familial isolated pituitary adenoma and was identified in two compound heterozygous asymptomatic males in this family who also carried the AIP p.R304* variant. Functional assessment of the effect of AIP binding with PDE4A5 did not demonstrate decreased binding compared to wildtype (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs148986773), ClinVar (classified as likely benign by GeneDx and Illumina and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as likely benign and a VUS) but was not identified in Cosmic. The variant was identified in control databases in 152 of 279364 chromosomes at a frequency of 0.0005441 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 119 of 126880 chromosomes (freq: 0.000938), Other in 5 of 7124 chromosomes (freq: 0.000702), Latino in 20 of 35308 chromosomes (freq: 0.000566) and African in 8 of 24522 chromosomes (freq: 0.000326), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. Expression of the p.A299V AIP protein expressed in HEK293 cells demonstrated a decreased half-life compared to expression of WT AIP (Hernández-Ramírez_2016_PMID:27253664). The p.Ala240 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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.