Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Tartaglia Lab, |
RCV000754387 | SCV000786636 | likely pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | 2018-04-01 | criteria provided, single submitter | research | |
Cole/Wambach Lab, |
RCV000754387 | SCV000886480 | pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | 2018-10-01 | criteria provided, single submitter | research | |
Broad Center for Mendelian Genomics, |
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, |
RCV000754387 | SCV001479503 | likely pathogenic | Neonatal pseudo-hydrocephalic progeroid syndrome | no assertion criteria provided | research |