rs191875469

Description

This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. This variant is present in population databases (rs191875469, gnomAD 0.2%). This variant has been observed in individual(s) with clinical features of POLR3A-related leukodystrophies (PMID: 27029625, 28459997, 29691679, 30323018, 30847471, 31637490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 445922). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28459997, 30323018). For these reasons, this variant has been classified as Pathogenic.

Identified in multiple unrelated patients with POLR3A-related disorders tested at GeneDx and in the published literature who had different pathogenic variants on the opposite allele (La Piana et al., 2016; Minnerop et al., 2017; Travaglini et al., 2018) Functional studies suggest this variant generates a "leaky" cryptic donor site that results in the inclusion of part of intron 14 (Minnerop et al., 2017) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect Observed in 0.1365% (386/282828 alleles) in large population cohorts (Lek et al., 2016).

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

The POLR3A c.1909+22G>A variant is an intronic variant. Across a selection of the available literature, the c.1909+22G>A variant has been identified in at least 30 unrelated individuals in a compound heterozygous state, all presenting with limb and gait ataxia. Tremor in the upper and lower limbs, dental problems, myopia, dysarthria, and dysphagia were also noted in some of these individuals. In addition, brain MRIs showed hyperintensities along the cerebellar peduncles, cervical cord atrophy, and hypoplasia of the corpus callosum (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Mild hypomyelination was also observed in some affected individuals (Rydning et al. 2019). The c.1909+22G>A variant was also present one individual in a homozygous state, primarily presenting with childhood-onset axonal neuropathy, in addition to gait ataxia (Minnerop et al. 2017). At least seven families had multiple affected individuals with the variant in a compound heterozygous state (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Evaluation of PCR products from affected individuals and healthy controls indicated that the variant affects splicing of exon 14, although this effect may be incomplete. In addition, inhibition of nonsense medicated mRNA decay in fibroblasts from affected individuals suggested the aberrantly spliced transcript due to the c.1909+22G>A variant is subject to nonsense mediated decay. In addition, gene and protein expression were reduced in the presence of the variant compared to controls (Minnerop et al. 2017). The c.1909+22G>A variant is reported at a frequency of 0.002238 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the c.1909+22G>A variant is classified as pathogenic for POLR3A-related neurological disorders.