Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ce |
RCV001171772 | SCV001334623 | likely pathogenic | not provided | 2020-03-01 | criteria provided, single submitter | clinical testing | |
Broad Institute Rare Disease Group, |
RCV002558722 | SCV003761145 | likely pathogenic | Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome | 2023-01-24 | criteria provided, single submitter | curation | The p.Tyr42Ter variant in POLR3A has not been previously reported in the literature in individuals with POLR3A-related disorders, but has been identified in 0.0009% (1/113758) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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#: 916218) and has been interpreted as likely pathogenic by CeGaT Center for Human Genetics Tuebingen. This nonsense variant leads to a premature termination codon at position 42, 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 for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). |