ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs267606539
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, 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 2022-02-28 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 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 58 of the AIP protein (p.Lys58Asn). This variant is present in population databases (rs267606539, gnomAD 0.002%). This missense change has been observed in individual(s) with pituitary adenoma (PMID: 21753072, 22319033, 23321498). ClinVar contains an entry for this variant (Variation ID: 41166). 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%. 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.
GeneDx RCV001038333 SCV003933386 uncertain significance not provided 2023-06-15 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; Observed in individuals with isolated sporadic pituitary adenomas (Tichomirowa et al., 2011; Cazabat et al., 2012); This variant is associated with the following publications: (PMID: 21753072, 23371967, 22319033, 23321498, 31351448)
Baylor Genetics RCV000034065 SCV004195316 uncertain significance Somatotroph adenoma 2023-10-06 criteria provided, single submitter clinical testing
GeneReviews RCV000034065 SCV000057995 not provided Somatotroph adenoma no assertion provided literature only

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