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

gnomAD frequency: 0.00001  dbSNP: rs751459271

Total submissions: 4

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853102	SCV002156624	uncertain significance	not provided	2024-11-11	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 (internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLR3B protein function with a positive predictive value of 80%. 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).
Ambry Genetics	RCV004649093	SCV005148939	uncertain significance	Inborn genetic diseases	2024-03-20	criteria provided, single submitter	clinical testing	The c.3173A>G (p.Y1058C) alteration is located in exon 27 (coding exon 27) of the POLR3B gene. This alteration results from a A to G substitution at nucleotide position 3173, causing the tyrosine (Y) at amino acid position 1058 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.