ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.736C>T (p.Arg246Cys)

gnomAD frequency: 0.00003  dbSNP: rs370258992
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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 RCV000130190 SCV000185027 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-31 criteria provided, single submitter clinical testing The p.R246C variant (also known as c.736C>T), located in coding exon 6 of the CDK4 gene, results from a C to T substitution at nucleotide position 736. The arginine at codon 246 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on one study that performed computational molecular modeling, this alterations is predicted to impact the structure and thermodynamics of the CDK4 protein (Nagasundaram N, et al. PLoS ONE 2015; 10(8):e0133969). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000810876 SCV000951113 uncertain significance Familial melanoma 2024-01-30 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 246 of the CDK4 protein (p.Arg246Cys). This variant is present in population databases (rs370258992, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of CDK4-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141602). 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%. 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 RCV002472951 SCV002769885 uncertain significance not provided 2023-05-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21520333, 26252490)

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