rs201314157

Description

In silico analysis suggests this variant may impact gene splicing. In the absence of additional RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28459997, 31940116, 32582862, 33559318, 33597727, 32860008, 32214227, 33098801)

Variant summary: POLR3A c.1771-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00011 in 251416 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in POLR3A causing Pol III-Related Leukodystrophy (0.00011 vs ND), allowing no conclusion about variant significance. c.1771-7C>G has been reported in the literature in multiple individuals affected with Pol III-Related Leukodystrophy. These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=8, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change falls in intron 13 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201314157, gnomAD 0.02%). This variant has been observed in individuals with POLR3A-related conditions (PMID: 28459997, 31940116, 32214227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449556). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 28459997). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.