ClinVar Miner

Submissions for variant NM_018082.6(POLR3B):c.986G>A (p.Arg329Gln)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002790008 SCV003761350 uncertain significance Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-02-24 criteria provided, single submitter curation The p.Arg329Gln variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 25131622) and has been identified in 0.0009% (1/113512) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID:rs1337382297). 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. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The number of missense variants reported in POLR3B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, the clinical significance of the p.Arg329Gln variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3_supporting, PP2 (Richards 2015).
Baylor Genetics RCV002790008 SCV004040669 likely pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2023-04-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004554025 SCV004118706 likely pathogenic POLR3B-related disorder 2024-07-12 no assertion criteria provided clinical testing The POLR3B c.986G>A variant is predicted to result in the amino acid substitution p.Arg329Gln. This variant has been reported in the compound heterozygous state in patients with POLR3B related autosomal recessive disease (Srivastava et al. 2014. PubMed ID: 25131622; PreventionGenetics internal data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

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