ClinVar Miner

Submissions for variant NM_003977.4(AIP):c.174G>C (p.Lys58Asn) (rs267606539)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000034065 SCV000373575 uncertain significance Somatotroph adenoma 2017-04-27 criteria provided, single submitter clinical testing The API c.174G>C (p.Lys58Asn) missense variant has been reported in at least two studies in which it is found in two patients with pituitary macroadenoma in a heterozygous state (Tichomirowa et al. 2011; Cazabat L. 2012). The p.Lys58Asn variant was absent from 360 controls but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on only two alleles but in a region of good sequence coverage. Based on the limited evidence, p.Lys58Asn variant is classified as a variant of uncertain significance but suspicious for pathogenicity for familial isolated pituitary adenomas. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ambry Genetics RCV001012978 SCV001173508 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-18 criteria provided, single submitter clinical testing The p.K58N variant (also known as c.174G>C), located in coding exon 2 of the AIP gene, results from a G to C substitution at nucleotide position 174. The lysine at codon 58 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in multiple individuals with pituitary macroadenoma (Tichomirowa MA et al. Eur. J. Endocrinol., 2011 Oct;165:509-15; Cazabat L et al. J. Clin. Endocrinol. Metab., 2012 Apr;97:E663-70; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001038333 SCV001201799 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 58 of the AIP protein (p.Lys58Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs267606539, ExAC 0.003%). This variant has been observed in individuals with pituitary adenoma (PMID: 21753072, 22319033, 23321498). ClinVar contains an entry for this variant (Variation ID: 41166). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 RCV000034065 SCV000057995 probable-pathogenic Somatotroph adenoma 2012-06-21 no assertion criteria provided curation Converted during submission to Likely pathogenic.

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