ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6446G>T (p.Arg2149Leu)

gnomAD frequency: 0.00006  dbSNP: rs201165149
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481341 SCV000569847 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing This variant is denoted POLE c.6446G>T at the cDNA level, p.Arg2149Leu (R2149L) at the protein level, and results in the change of an Arginine to a Leucine (CGC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg2149Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Arg2149Leu occurs at a position that is not conserved and is located in the zinc finger domains (Tahirov 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg2149Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000481341 SCV001224073 uncertain significance not provided 2024-12-24 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 2149 of the POLE protein (p.Arg2149Leu). This variant is present in population databases (rs201165149, gnomAD 0.02%). 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: 420849). 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.

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