ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.3206G>A (p.Arg1069Gln)

gnomAD frequency: 0.00002  dbSNP: rs778985686
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Total submissions: 4
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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 RCV000754380 SCV000786629 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2018-04-01 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV001815367 SCV002062927 likely pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003488778 SCV004232662 uncertain significance Leukodystrophy 2024-01-24 criteria provided, single submitter curation The p.Arg1069Gln variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30323018), and has been identified in 0.01% (2/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs778985686). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 549558) and has been interpreted as likely pathogenic or pathogenic by Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital), OMIM, and CeGaT Center for Human Genetics Tuebingen. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Asp1292Asn variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 30323018). In summary, the clinical significance of the p.Arg1069Gln variant is uncertain. ACMG/AMP Criteria applied: PM3, PM1_supporting (Richards 2015).
OMIM RCV000754380 SCV000883062 pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2022-05-24 no assertion criteria provided literature only

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