ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3443C>G (p.Pro1148Arg)

gnomAD frequency: 0.00001  dbSNP: rs1060500886
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001764380 SCV000544218 uncertain significance not provided 2024-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1148 of the POLE protein (p.Pro1148Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405891). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. 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 RCV001764380 SCV001999467 uncertain significance not provided 2019-11-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002451084 SCV002614686 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-19 criteria provided, single submitter clinical testing The p.P1148R variant (also known as c.3443C>G), located in coding exon 28 of the POLE gene, results from a C to G substitution at nucleotide position 3443. The proline at codon 1148 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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