ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.2422C>T (p.Arg808Ter)

gnomAD frequency: 0.00001  dbSNP: rs750874617
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000994467 SCV001148004 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Invitae RCV000994467 SCV002232704 pathogenic not provided 2022-08-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 806529). This variant has not been reported in the literature in individuals affected with POLR3A-related conditions. This variant is present in population databases (rs750874617, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg808*) in the POLR3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527).
Broad Institute Rare Disease Group, Broad Institute RCV002549871 SCV003761132 likely pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2023-01-24 criteria provided, single submitter curation The p.Arg808Ter variant in POLR3A has been reported in 1 individual, with POLR3A-related disorders (PMID: 35578252) and has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750874617). 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#: 806529) and has been interpreted as pathogenic or likely pathogenic by CeGaT Center for Human Genetics Tuebingen and Invitae. This nonsense variant leads to a premature termination codon at position 808, which is 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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