ClinVar Miner

Submissions for variant NM_018082.6(POLR3B):c.1648C>T (p.Arg550Ter)

gnomAD frequency: 0.00003  dbSNP: rs267608688
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002243660 SCV002512891 pathogenic not provided 2022-04-22 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (cells expressing R550X failed to differentiate morphologically and phosphorylation/activation levels of molecules associated with mTOR signaling were decreased) (Sawaguchi et al., 2022); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22855961, 18851904, 22036171, 27535533, 35225888)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000024158 SCV003761426 pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-02-24 criteria provided, single submitter curation The p.Arg550Ter variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036171), and has been identified in 0.003% (1/34550) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608688). 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#: 31162) and has been interpreted as pathogenic by GeneReviews and OMIM. In vitro functional studies provide some evidence that the p.Arg550Ter variant may impact protein function (PMID: 22036171). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 550, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PS3_moderate, PM2_supporting (Richards 2015).
Baylor Genetics RCV000024158 SCV003836119 pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-03-21 criteria provided, single submitter clinical testing
OMIM RCV000024158 SCV000045449 pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2011-11-11 no assertion criteria provided literature only
GeneReviews RCV000024158 SCV000055917 not provided Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism no assertion provided literature only
Undiagnosed Diseases Network, NIH RCV000024158 SCV003915639 pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-04-01 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.