ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.3944_3945del (p.Val1315fs)

dbSNP: rs1378008503
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001267909 SCV001446416 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Invitae RCV001267909 SCV002243153 pathogenic not provided 2022-11-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with spastic ataxia (PMID: 28459997). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Val1315Alafs*7) 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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002542854 SCV003761117 pathogenic Leukodystrophy 2023-01-24 criteria provided, single submitter curation The p.Val1315fs variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with hypomyelinating leukodystrophy (PMID: 28459997), and has been identified in 0.002% (2/113620) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs901741607). 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#: 986804) and has been interpreted as pathogenic by Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen) and Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1315 and leads to a premature termination codon 7 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hypomyelinating leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015).

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