ClinVar Miner

Submissions for variant NM_018082.6(POLR3B):c.3317T>C (p.Ile1106Thr)

gnomAD frequency: 0.00001  dbSNP: rs765382317
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485220 SCV000566711 likely pathogenic not provided 2023-09-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28252636)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002525788 SCV003761452 uncertain significance Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-02-28 criteria provided, single submitter curation The p.Ile1106Thr variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 28252636), and has been identified in 0.004% (4/113690) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765382317). 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#: 419123) and has been interpreted as likely pathogenic by GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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.Ile1106Thr variant is uncertain. ACMG/AMP Criteria applied: PP3, PP2, PM2_supporting (Richards 2015).

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