Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000414392 | SCV000491316 | likely pathogenic | not provided | 2016-06-08 | criteria provided, single submitter | clinical testing | The E644K variant in the POLR3A gene has been reported previously in three unrelated patients with hypomyelinating leukodystrophy who were heterozygous for the E644K variant and heterozygous for another variant (Wolf et al., 2014). The E644K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E644K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The E644K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
Invitae | RCV000414392 | SCV002188167 | uncertain significance | not provided | 2021-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 644 of the POLR3A protein (p.Glu644Lys). This variant is present in population databases (rs755165065, gnomAD 0.002%). This missense change has been observed in individuals with POLR3-related leukodystrophy (PMID: 25339210). ClinVar contains an entry for this variant (Variation ID: 372801). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. |
Ambry Genetics | RCV002524641 | SCV003740382 | uncertain significance | Inborn genetic diseases | 2022-09-30 | criteria provided, single submitter | clinical testing | The c.1930G>A (p.E644K) alteration is located in exon 15 (coding exon 15) of the POLR3A gene. This alteration results from a G to A substitution at nucleotide position 1930, causing the glutamic acid (E) at amino acid position 644 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Broad Institute Rare Disease Group, |
RCV001541990 | SCV004232683 | uncertain significance | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | 2024-01-24 | criteria provided, single submitter | curation | The p.Glu644Lys variant in POLR3A has been reported in 3 individuals with POLR3A-related disorders (PMID: 25339210), and has been identified in 0.003% (3/113746) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755165065). 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#: 372801) and has been interpreted as pathogenic or likely pathogenic by GeneReviews and GeneDx, and as a variant of uncertain significance by Invitae. 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, the clinical significance of the p.Glu644Lys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015). |
Gene |
RCV001541990 | SCV001760627 | not provided | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | no assertion provided | literature only |