ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5476C>T (p.Arg1826Trp)

gnomAD frequency: 0.00001  dbSNP: rs762000608
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759306 SCV000836781 uncertain significance not provided 2024-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1826 of the POLE protein (p.Arg1826Trp). This variant is present in population databases (rs762000608, gnomAD 0.01%). 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: 583360). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759306 SCV000888553 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000759306 SCV003809183 uncertain significance not provided 2019-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000759306 SCV005376279 uncertain significance not provided 2024-04-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: variant designated functionally abnormal based on an in vitro assay measuring cell survival (PMID: 34749799); This variant is associated with the following publications: (PMID: 34749799)

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