ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs587778185
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Total submissions: 6
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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 Melanoma, cutaneous malignant, susceptibility to, 3 2018-03-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000815362 SCV000955811 uncertain significance Familial melanoma 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the CDK4 protein (p.Arg122Cys). This variant is present in population databases (rs587778185, gnomAD 0.006%). 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: 133874). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV001020800 SCV001182327 likely benign Hereditary cancer-predisposing syndrome 2024-12-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc. RCV000663084 SCV004020073 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 3 2023-03-07 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
ITMI RCV000120534 SCV000084687 not provided not specified 2013-09-19 no assertion provided reference population

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