ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.2542T>C (p.Phe848Leu)

gnomAD frequency: 0.00001  dbSNP: rs1211210077
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001359714 SCV001555594 uncertain significance not provided 2022-11-08 criteria provided, single submitter clinical testing 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. 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 not expected to disrupt POLR3A protein function. ClinVar contains an entry for this variant (Variation ID: 1051646). This missense change has been observed in individuals with leukodystrophy (PMID: 25339210; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 848 of the POLR3A protein (p.Phe848Leu).
GeneDx RCV001359714 SCV001986298 uncertain significance not provided 2020-12-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25339210)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003490220 SCV004232670 uncertain significance Leukodystrophy 2024-01-24 criteria provided, single submitter curation The p.Phe848Leu variant in POLR3A has been reported in one individual, in the homozygous state, with hypomyelinating leukodystrophy (PMID: 25339210), and has been identified in 0.003% (1/34578) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1211210077). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1051646) and has been interpreted as pathogenic by GeneReviews and as a variant of uncertain significance by Invitae and GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_supporting (Richards 2015).
GeneReviews RCV001541999 SCV001760637 not provided Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome no assertion provided literature only

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