ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.2119C>T (p.Gln707Ter)

gnomAD frequency: 0.00001  dbSNP: rs780839834
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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
MyeliNeuroGene Lab, McGill University Health Center Research Institute RCV000845267 SCV000987272 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome criteria provided, single submitter research
Broad Institute Rare Disease Group, Broad Institute 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).

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