ClinVar Miner

Submissions for variant NM_004064.5(CDKN1B):c.118G>A (p.Glu40Lys)

gnomAD frequency: 0.00001  dbSNP: rs765527234
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002254867 SCV002526072 uncertain significance Multiple endocrine neoplasia type 4 2022-05-16 criteria provided, single submitter clinical testing The CDKN1B c.118G>A (p.Glu40Lys) missense change has a maximum subpopulation frequency of 0.0058% in gnomAD v2.1.1. In silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 4. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Ambry Genetics RCV002337416 SCV002643533 likely benign Hereditary cancer-predisposing syndrome 2022-04-27 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV002254867 SCV005822478 uncertain significance Multiple endocrine neoplasia type 4 2024-08-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 40 of the CDKN1B protein (p.Glu40Lys). This variant is present in population databases (rs765527234, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDKN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1691538). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN1B function (PMID: 28425505). 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.

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