ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.364C>T (p.Arg122Cys) (rs587778185)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656826 SCV000564849 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.364C>T at the cDNA level, p.Arg122Cys (R122C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Arg122Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDK4 Arg122Cys is located in the protein kinase domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDK4 Arg122Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000663084 SCV000786168 uncertain significance Cutaneous malignant melanoma 3 2018-03-12 criteria provided, single submitter clinical testing
Invitae RCV000815362 SCV000955811 uncertain significance Hereditary melanoma 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 122 of the CDK4 protein (p.Arg122Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587778185, ExAC 0.009%). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 133874). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C3. The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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. 5
Ambry Genetics RCV001020800 SCV001182327 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing The p.R122C variant (also known as c.364C>T), located in coding exon 3 of the CDK4 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar 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.
ITMI RCV000120534 SCV000084687 not provided not specified 2013-09-19 no assertion provided reference population

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