ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.803A>G (p.Tyr268Cys) (rs267606577)

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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 RCV001027096 SCV001189601 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing The p.Y268C variant (also known as c.803A>G), located in coding exon 6 of the AIP gene, results from an A to G substitution at nucleotide position 803. The tyrosine at codon 268 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with apparent sporadic pituitary macroadenomas (Tichomirowa MA et al. Eur. J. Endocrinol., 2011 Oct;165:509-15; Beckers A et al. Endocr. Rev., 2013 Apr;34:239-77). This alteration is located in the functional significant tetratricopeptide repeat domain of the AIP protein, and a structural analysis suggests it may disrupt packing of the hydrophobic core (Morgan RM et al. PLoS ONE, 2012 Dec;7:e53339). 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.
Invitae RCV001341744 SCV001535633 uncertain significance not provided 2020-02-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 268 of the AIP protein (p.Tyr268Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with a prolactinoma (PMID: 21753072). ClinVar contains an entry for this variant (Variation ID: 41206). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000034105 SCV000058035 probable-pathogenic Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Likely pathogenic.

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