ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.133G>A (p.Gly45Ser) (rs876660318)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215220 SCV000277646 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-07 criteria provided, single submitter clinical testing The p.G45S variant (also known as c.133G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 133. The glycine at codon 45 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 17000alleles tested) in our clinical cohort.This amino acid position is poorly 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 p.G45Sremains unclear.
Invitae RCV000638973 SCV000760530 uncertain significance Hereditary melanoma 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 45 of the CDK4 protein (p.Gly45Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 233299). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine 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.

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