ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.409G>C (p.Val137Leu) (rs150281463)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204954 SCV000261093 uncertain significance Hereditary melanoma 2020-07-26 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 137 of the CDK4 protein (p.Val137Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs150281463, ExAC 0.01%). This variant has not been reported in the literature in individuals with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 220499). 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. 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 RCV000483166 SCV000571760 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.409G>C at the cDNA level, p.Val137Leu (V137L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant has been observed in at least one individual with advanced cancer (Mandelker 2017). CDK4 Val137Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the protein kinase domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDK4 Val137Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573964 SCV000669104 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-17 criteria provided, single submitter clinical testing The p.V137L variant (also known as c.409G>C), located in coding exon 3 of the CDK4 gene, results from a G to C substitution at nucleotide position 409. The valine at codon 137 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483166 SCV000889265 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing

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