ClinVar

Description

The p.Val1315fs variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with hypomyelinating leukodystrophy (PMID: 28459997), and has been identified in 0.002% (2/113620) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs901741607). 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#: 986804) and has been interpreted as pathogenic by Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen) and Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1315 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive hypomyelinating leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hypomyelinating leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015).