ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs587778184
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Total submissions: 4
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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 2023-05-14 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 Familial melanoma 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 85 of the CDK4 protein (p.Arg85Gln). This variant is present in population databases (rs587778184, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 133873). 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 CDK4 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120533 SCV002571896 uncertain significance not specified 2022-08-09 criteria provided, single submitter clinical testing Variant summary: CDK4 c.254G>A (p.Arg85Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.254G>A in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000120533 SCV000084686 not provided not specified 2013-09-19 no assertion provided reference population

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