ClinVar Miner

Submissions for variant NM_018082.6(POLR3B):c.3173A>G (p.Tyr1058Cys)

gnomAD frequency: 0.00001  dbSNP: rs751459271
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193260 SCV000248569 likely pathogenic Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2014-12-05 criteria provided, single submitter clinical testing
Invitae RCV001853102 SCV002156624 uncertain significance not provided 2022-07-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1058 of the POLR3B protein (p.Tyr1058Cys). This variant is present in population databases (rs751459271, gnomAD 0.03%). This missense change has been observed in individual(s) with leukodystrophy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 211934). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000193260 SCV003761450 uncertain significance Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism 2022-02-28 criteria provided, single submitter curation The p.Tyr1058Cys variant in POLR3B has not been previously reported in the literature in individuals with 4H leukodystrophy but has been identified in 0.03% (9/34588) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs751459271). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 211934) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). 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.Tyr1058Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PP2 (Richards 2015).

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