ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.254G>A (p.Arg85Gln) (rs587778184)

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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 RCV000563086 SCV000669148 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.R85Q variant (also known as c.254G>A), located in coding exon 2 of the CDK4 gene, results from a G to A substitution at nucleotide position 254. The arginine at codon 85 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE 2014 Apr;9:e94554). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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 RCV000803516 SCV000943394 uncertain significance Hereditary melanoma 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 85 of the CDK4 protein (p.Arg85Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587778184, ExAC 0.01%). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 133873). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ITMI RCV000120533 SCV000084686 not provided not specified 2013-09-19 no assertion provided reference population

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