Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000498819 | SCV000590341 | likely pathogenic | not provided | 2022-01-17 | criteria provided, single submitter | clinical testing | Non-canonical splice variant results in abnormal splicing leading to an in-frame deletion of exon 26 with an unclear effect on protein function (Lessel et al., 2018; Wambach et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30414627, 30450527, 25898808) |
Cole/Wambach Lab, |
RCV000755669 | SCV000886473 | pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | 2018-10-01 | criteria provided, single submitter | research | |
Broad Institute Rare Disease Group, |
RCV003488638 | SCV004232661 | likely pathogenic | Leukodystrophy | 2024-01-24 | criteria provided, single submitter | curation | The c.3337-5T>A variant in POLR3A has been reported in 5 individuals with POLR3A-related disorders (PMID: 30414627, 30450527), and has been identified in 0.001% (1/11858) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs368905417). 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#: 432594) and has been interpreted as likely pathogenic or pathogenic by multiple labs. Of the 5 affected individuals, 1 was a compound heterozygote that carried a likely pathogenic variants in trans, which increases the likelihood that the c.3337-5T>A variant is pathogenic (VariationID: 619036; PMID: 30414627). In vitro functional studies provide some evidence that the c.3337-5T>A variant may impact protein function (PMID: 30414627, 30450527). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. 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: PM3, PP3, PS3_moderate, PM2_supporting (Richards 2015). |
OMIM | RCV000755669 | SCV000883071 | pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | 2015-08-01 | no assertion criteria provided | literature only | |
University of Washington Center for Mendelian Genomics, |
RCV001291254 | SCV001479679 | likely pathogenic | Wiedemann-Rautenstrauch-like progeroid syndrome | no assertion criteria provided | research | ||
University of Washington Center for Mendelian Genomics, |
RCV000755669 | SCV001479783 | likely pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | no assertion criteria provided | research |