ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5516G>A (p.Arg1839His)

gnomAD frequency: 0.00006  dbSNP: rs370512955
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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 RCV003540500 SCV000772656 uncertain significance not provided 2024-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1839 of the POLE protein (p.Arg1839His). This variant is present in population databases (rs370512955, gnomAD 0.008%). 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: 540704). 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.
GeneDx RCV003540500 SCV005080795 uncertain significance not provided 2023-12-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified by whole-exome sequencing in individual(s) with severe specific language impairment (PMID: 28440294); This variant is associated with the following publications: (PMID: 28440294)
Fulgent Genetics, Fulgent Genetics RCV005004300 SCV005633681 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-06-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004737931 SCV005361092 uncertain significance POLE-related disorder 2024-05-04 no assertion criteria provided clinical testing The POLE c.5516G>A variant is predicted to result in the amino acid substitution p.Arg1839His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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