ClinVar

Description

Variant summary: POLR3A c.760C>T (p.Arg254X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251396 control chromosomes. c.760C>T has been reported in the literature at a compound heterozygous state with a second pathogenic variant in at-least one individual affected with Wiedemann-Rautenstrauch Syndrome (example, Wambach_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. These data indicate that the variant is very likely associated with POLR3A-associated diseases including Wiedemann-Rautenstrauch Syndrome and Pol III-Related Leukodystrophy. The following publication has been ascertained in the context of this evaluation (PMID: 30414627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.