ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.3337-5T>A

gnomAD frequency: 0.00001  dbSNP: rs368905417
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, Washington University in St. Louis RCV000755669 SCV000886473 pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2018-10-01 criteria provided, single submitter research
Broad Institute Rare Disease Group, Broad Institute 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, University of Washington RCV001291254 SCV001479679 likely pathogenic Wiedemann-Rautenstrauch-like progeroid syndrome no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000755669 SCV001479783 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome no assertion criteria provided research

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