Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clinical Genetics and Genomics, |
RCV001269672 | SCV001449832 | likely pathogenic | not provided | 2016-01-12 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001269672 | SCV003483996 | pathogenic | not provided | 2022-02-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 988361). This premature translational stop signal has been observed in individual(s) with hereditary ataxia and spastic paraparesis (PMID: 30847471). This variant is present in population databases (rs755978559, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gly1219*) in the POLR3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527). |
Broad Institute Rare Disease Group, |
RCV002537725 | SCV003761121 | pathogenic | Leukodystrophy | 2023-01-24 | criteria provided, single submitter | curation | The p.Gly1219Ter variant in POLR3A has been reported in 8 individuals with POLR3A-related disorders, segregated with disease in 2 affected relatives from 2 families (PMID: 30847471), and has been identified in 0.003% (3/113580) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755978559). 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: 988361) and has been interpreted as likely pathogenic by Clinical Genetics Karolinska University Hospital (Karolinska University Hospital). Of the 8 affected individuals, all were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly1219Ter variant is pathogenic (VariationID: 445922; PMID: 30847471). This nonsense variant leads to a premature termination codon at position 1219, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PP1, PM2_supporting (Richards 2015). |