ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3818G>T (p.Arg1273Leu)

dbSNP: rs377324348
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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 RCV003654342 SCV000544159 uncertain significance not provided 2024-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1273 of the POLE protein (p.Arg1273Leu). 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: 405834). 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 not expected to disrupt POLE protein function with a negative 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.
PreventionGenetics, part of Exact Sciences RCV004529589 SCV004108991 uncertain significance POLE-related disorder 2023-04-27 criteria provided, single submitter clinical testing The POLE c.3818G>T variant is predicted to result in the amino acid substitution p.Arg1273Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405834/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx RCV003654342 SCV005327777 uncertain significance not provided 2023-06-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29641532)

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