Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000494591 | SCV000583024 | likely pathogenic | not provided | 2015-11-28 | criteria provided, single submitter | clinical testing | The Q707X variant in the POLR3A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q707X 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. Protein truncating pathogenic variants downstream of this variant have been reported in the Human Gene Mutation Database in association with POLR3A-related disorders (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. We interpret Q707X as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded |
Myeli |
RCV000845267 | SCV000987272 | pathogenic | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | criteria provided, single submitter | research | ||
Broad Institute Rare Disease Group, |
RCV000845267 | SCV003761134 | likely pathogenic | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | 2023-01-24 | criteria provided, single submitter | curation | The p.Gln707Ter variant in POLR3A has been reported in 1 individual with POLR3A-related disorders (PMID: 32582862), and has been identified in 0.002% (2/113746) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs780839834). 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#: 430255) and has been interpreted as pathogenic or likely pathogenic by GeneDx and MyeliNeuroGene Lab (McGill University Health Center Research Institute). This nonsense variant leads to a premature termination codon at position 707, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). |