ClinVar

Description

The p.Pro50fs variant in POLR3A has not been previously reported in the literature in individuals with hypomyelinating leukodystrophy, but has been identified in 0.007% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs746680609). 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#: 1453734) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 50 and leads to a premature termination codon 10 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hypomyelinating leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).