ClinVar Genomic variation as it relates to human health

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLR3B-related disorder (ClinVar ID: VCV001184067 / PMID: 25339210). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

The p.Val667Met variant in POLR3B has been reported in 2 compound heterozygous individuals with 4H leukodystrophy (PMID: 25339210, 31969655), and has been identified in 0.004% (1/24960) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756536922). 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. Of the 2 affected individuals, 1 was a compound heterozygote that carried a variant of uncertain significance in trans and 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Val667Met variant is pathogenic (PMID: 31969655, 25339210; Clinvar ID: 419962). This variant has also been reported in ClinVar (Variation ID#: 1184067) and has been interpreted as VUS by GeneDx and pathogenic by GeneReviews. 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.Val667Met variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PP2, PM3_supporting (Richards 2015).

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31969655, 25339210)

The missense variant p.V667M in POLR3B (NM_018082.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.V667M variant is observed in 1/16,256 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene POLR3B contains 12 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.V667M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 667 of POLR3B is conserved in all mammalian species. The nucleotide c.1999 in POLR3B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 667 of the POLR3B protein (p.Val667Met). This variant is present in population databases (rs756536922, gnomAD 0.004%). This missense change has been observed in individuals with POLR3B-related conditions (PMID: 25339210, 31969655). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1184067). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLR3B protein function. 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.

This missense variant (c.1999G>A, p.Val667Met) has not been observed in population databases (gnomAD). The change has been reported in the literature (PMID 31969655, PMID 25339210). Variant prediction programs suggest a deleterious effect, but no functional studies have been published. It was found in an affected individual who is also heterozygous for a variant of uncertain significance (c.2644A>C, p.Lys882Gln), but no parental testing was performed.