ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.3874G>A (p.Asp1292Asn)

gnomAD frequency: 0.00001  dbSNP: rs757209071
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Total submissions: 3
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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 RCV000754393 SCV000786644 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2018-05-01 criteria provided, single submitter research
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) RCV003387902 SCV003920805 likely pathogenic POLR3A-related disorder 2023-04-27 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003488782 SCV004232693 uncertain significance Leukodystrophy 2024-01-24 criteria provided, single submitter curation The p.Asp1292Asn variant in POLR3A has been reported in 1 individual with POLR3A-related disorders but has been identified in 0.005% (1/21636) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757209071). 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#: 549571) and has been interpreted as likely pathogenic by Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital). 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/functional domain and slightly supports pathogenicity (PMID: 30323018). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM1_supporting, PM2_supporting (Richards 2015).

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