ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.100C>T (p.Arg34Cys)

gnomAD frequency: 0.00001  dbSNP: rs771051323
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002249799 SCV001381669 uncertain significance not provided 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the POLE protein (p.Arg34Cys). This variant is present in population databases (rs771051323, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome and poikiloderma (PMID: 32705701). ClinVar contains an entry for this variant (Variation ID: 940582). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 RCV002249799 SCV002520226 uncertain significance not provided 2022-05-20 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; Observed in homozygous state in a patient and sibling with clinical features of facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome and poikiloderma (Eason 2020); This variant is associated with the following publications: (PMID: 25228659, 27244218, 33477564, 31829442, 32705701)
PreventionGenetics, part of Exact Sciences RCV003963126 SCV004782838 uncertain significance POLE-related condition 2023-12-27 criteria provided, single submitter clinical testing The POLE c.100C>T variant is predicted to result in the amino acid substitution p.Arg34Cys. This variant was reported in the homozygous state in an individual with Facial dysmorphism, Immunodeficiency, Livedo & Short stature (FILS) syndrome (Eason et al. 2020. PubMed ID: 32705701). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) 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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