ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.1046_1047del (p.Gln349fs)

gnomAD frequency: 0.00001  dbSNP: rs754820097
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DASA RCV001836686 SCV002097314 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2022-02-14 criteria provided, single submitter clinical testing The c.1046_1047del;p.(Gln349Argfs*4) is a null frameshift variant in the POLR3A gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant is present at low allele frequencies population databases (rs754820097 - gnomAD 0.00006574%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002542787 SCV003761140 likely pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2023-01-24 criteria provided, single submitter curation The p.Gln349fs variant in POLR3A has not been previously reported in the literature in individuals with POLR3A-related disorders, but has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1373306947). 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#: 1341525) and has been interpreted as likely pathogenic by DASA. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 349 and leads to a premature termination codon 4 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 POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

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