ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypomyelinating leukodystrophy 7, with or without oligodontia and/or hypogonadotropic hypogonadism (MIM# 607694), Wiedemann-Rautenstrauch syndrome (MIM#264090) and POLR3A-related spastic ataxia (PMID: 31637490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability in individuals with a leukodystrophy phenotype have been reported (PMID: 21855841). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. cDNA analysis using a peripheral blood RNA sample from an affected individual with this variant showed exon 26 skipping, resulting in p.(Ile1113_Glu1143del) (PMID: 30414627). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is expected to disrupt the RNA_pol_Rpb1_5 domain (DECIPHER). (I) 0703 - Another splice site variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. c.3337-5T>A, which has been shown to cause exon 26 skipping, has been reported in multiple individuals with Wiedemann-Rautenstrauch syndrome (PMID: 30414627). The variant has also been reported as likely pathogenic by a clinical testing laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in four unrelated individuals with Wiedemann-Rautenstrauch syndrome (PMIDs: 30414627, 32555393, 36825045). In three of those individuals, the variant has been reported to be compound heterozygous with another splice or NMD-predicted variant. It has also been reported as pathogenic by two clinical testing laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change falls in intron 25 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30323018, 30414627, 32555393). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 549559). Studies have shown that this variant results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 30414627). For these reasons, this variant has been classified as Pathogenic.

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Intron variant In silico tools do not predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.05 (<=0.1, moderate evidence for non-spliceogenicity)]. However, it is reported to alter splicing, resulting in an in-frame exon 26 deletion (PMID: 30414627) The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 30414627). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000549559 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

POLR3A: PM3:Very Strong, PM2, PS3:Supporting