ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.133G>T (p.Gly45Cys)

dbSNP: rs876660318
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236649 SCV000293787 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.133G>T at the cDNA level, p.Gly45Cys (G45C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Gly45Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Gly45Cys occurs at a position that is not conserved and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDK4 Gly45Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV003746507 SCV004434910 uncertain significance Familial melanoma 2023-01-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 246297). 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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 45 of the CDK4 protein (p.Gly45Cys).

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