Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000441182 | SCV000521466 | likely pathogenic | not provided | 2015-12-15 | criteria provided, single submitter | clinical testing | The G914E variant in the POLR3A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This 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 G914E 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 G914E variant is a strong candidate for a pathogenic variant. |
Broad Institute Rare Disease Group, |
RCV003488592 | SCV004232665 | uncertain significance | Leukodystrophy | 2024-01-24 | criteria provided, single submitter | curation | The p.Gly914Glu variant in POLR3A has not been previously reported in individuals with POLR3A-related disorders, but has been identified in 0.003% (1/34590) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747257894). 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#: 381806) and has been interpreted as likely pathogenic by GeneDx. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly914Glu variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015). |