Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Broad Center for Mendelian Genomics, |
RCV000024139 | SCV004232679 | likely pathogenic | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | 2024-01-24 | criteria provided, single submitter | curation | The p.Gly672Glu variant in POLR3A has been reported in 7 individuals with POLR3A-related disorders (PMID: 21855841, 33005949, 25339210), and has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608670). 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. Of the 7 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Gly672Glu variant is pathogenic (PMID: 21855841, 33005949). This variant has also been reported in ClinVar (Variation ID#: 31143) and has been interpreted as pathogenic by GeneReviews and OMIM. 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.Gly672Glu variant is uncertain. ACMG/AMP Criteria applied: PM3, PM2_supporting, PP3 (Richards 2015). |
Prevention |
RCV003934851 | SCV004749462 | likely pathogenic | POLR3A-related condition | 2024-01-01 | criteria provided, single submitter | clinical testing | The POLR3A c.2015G>A variant is predicted to result in the amino acid substitution p.Gly672Glu. This variant was reported both in the homozygous and compound heterozygous states in patients with hypomyelinating leukodystrophy (Bernard et al. 2011. PubMed ID: 21855841; Supplementary table e-1, Wolf et al. 2014. PubMed ID: 25339210). A recent study reviewed that this variant in the homozygous state did present typical neurological features of hypomyelinating leukodystrophy (4H leukodystrophy), although transgenic mouse models of this variant (in the homozygous state or in the compound heterozygous state with one null allele) did not demonstrate the phenotype of childhood-onset hypomyelinating leukodystrophy (Pelletier et al. 2021. PubMed ID: 33005949; Choquet et al. 2017. PubMed ID: 28407788). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Based on the given information, this variant is classified as likely pathogenic. |
OMIM | RCV000024139 | SCV000045430 | pathogenic | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | 2011-09-09 | no assertion criteria provided | literature only | |
Gene |
RCV000024139 | SCV000055885 | not provided | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | no assertion provided | literature only |