Submissions for variant NM_018082.6(POLR3B):c.2278G>A (p.Ala760Thr)

gnomAD frequency: 0.00001  dbSNP: rs146513209

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095759	SCV001251602	likely pathogenic	Pol III-related leukodystrophy	2020-02-06	criteria provided, single submitter	clinical testing	The POLR3B c.2278G>A (p.Ala760Thr) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were identified through this search. The p.Ala760Thr variant is reported at a frequency of 0.000023 in the European (non-Finnish) population of the Genome Aggregation Database, indicating it is rare. Based on the application of the AMCG criteria, including the potential impact of missense variants in the POLR3B gene, the rarity of the p.Ala760Thr variant, the p.Ala760Thr variant is classified as likely pathogenic for Pol III-related leukodystrophy.
GeneDx	RCV002254951	SCV002526274	likely pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34737199, 27535533)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002554882	SCV003761436	likely pathogenic	Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism	2022-02-28	criteria provided, single submitter	curation	The p.Ala760Thr variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 34737199), and has been identified in 0.002% (3/128476) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs146513209). 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#: 873511) and has been interpreted as likely pathogenic by Illumina Clinical Services Laboratory (Illumina). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive 4H leukodystrophy. ACMG/AMP Criteria applied: PM2, PM3, PP2, PP3 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV002254951	SCV004131817	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	POLR3B: PM2, PP2, PP3
Invitae	RCV002254951	SCV004560422	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLR3B protein function. ClinVar contains an entry for this variant (Variation ID: 873511). This variant has not been reported in the literature in individuals affected with POLR3B-related conditions. This variant is present in population databases (rs146513209, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 760 of the POLR3B protein (p.Ala760Thr).