ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.3G>T (p.Met1Ile)

dbSNP: rs1168641193
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital RCV000754387 SCV000786636 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2018-04-01 criteria provided, single submitter research
Cole/Wambach Lab, Washington University in St. Louis RCV000754387 SCV000886480 pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2018-10-01 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003485628 SCV004232699 likely pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2024-01-24 criteria provided, single submitter curation The p.Met1Ile variant in POLR3A has been reported in 3 individuals with POLR3A-related disorders (PMID: 30323018, 30414627, 30450527) and has been identified in 0.003% (1/34586) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1168641193). 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#: 549565) and has been interpreted as pathogenic or likely pathogenic by Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital), OMIM, Cole/Wambach Lab (Washington University in St. Louis), and University of Washington Center for Mendelian Genomics (University of Washington). Of the 3 affected individuals, 2 were compound heterozygotes that carried a reported variant of uncertain significance in trans, which increases the likelihood that the p.Met1Ile variant is pathogenic (Variant ID: 549564; PMID: 30323018, 30414627). This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 22 and there are no reported pathogenic or likely pathogenic variants in ClinVar upstream of this methionine. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1_strong, PM3_supporting, PM2_supporting (Richards 2015).
OMIM RCV000754387 SCV000883068 pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2022-05-24 no assertion criteria provided literature only
University of Washington Center for Mendelian Genomics, University of Washington RCV000754387 SCV001479503 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome no assertion criteria provided research

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