ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.308A>G (p.Lys103Arg) (rs267606548)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001018537 SCV001179789 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing The p.K103R variant (also known as c.308A>G), located in coding exon 3 of the AIP gene, results from an A to G substitution at nucleotide position 308. The lysine at codon 103 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Isolated Pituitary Adenomas (FIPA) (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60; Stratakis CA et al. Clin. Genet. 2010 Nov;78:457-63; Guaraldi F et al. Clin Transl Sci. 2011 Feb;4:55-62; Beckers A et al. Endocr. Rev. 2013 Apr;34:239-77; Dinesen PT et al. Endocrinol Diabetes Metab Case Rep. 2015 Jan;2015:140105). Further, functional analysis using a yeast two-hybrid quantitative b-galactosidase assay assessed the interaction of AIP with PDE4A5, an AIP binding protein, and found that this alteration results in b-galactosidase assay activity values more than fivefold different from wild type suggesting that it leads to a complete loss of PDE4A5–AIP binding (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). However another functional analysis using protein expression of the PDE4A5 rat homologue PDE4A4, suggests the p.K103R alteration has no clear inhibitory effect (Bolger GB et al. Endocr. Relat. Cancer, 2016 May;23:419-31). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001214294 SCV001385969 uncertain significance not provided 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 103 of the AIP protein (p.Lys103Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ACTH-secreting microadenoma (PMID: 20507346). ClinVar contains an entry for this variant (Variation ID: 41174). This variant has been reported to have conflicting or insufficient data to determine the effect on AIP protein function (PMID: 20506337, 28255869). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneReviews RCV000034073 SCV000058003 probable-pathogenic Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Likely pathogenic.

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