Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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 | |
Gene |
RCV000024158 | SCV000055917 | not provided | Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism | no assertion provided | literature only | ||
Undiagnosed Diseases Network, |
RCV000024158 | SCV003915639 | pathogenic | Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism | 2022-04-01 | no assertion criteria provided | clinical testing |