ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.2423G>A (p.Arg808Gln)

dbSNP: rs374831450
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001330346 SCV001521995 likely pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2019-10-03 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in one affected individual [PMID: 29618326]
Invitae RCV002546384 SCV003460064 uncertain significance not provided 2022-08-11 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1029126). This missense change has been observed in individual(s) with POLR3-related leukodystrophy (PMID: 29618326). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 808 of the POLR3A protein (p.Arg808Gln).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003490195 SCV004232674 uncertain significance Leukodystrophy 2024-01-24 criteria provided, single submitter curation The p.Arg808Gln variant in POLR3A has been reported, in the homozygous state, in 1 individual with hypomyelinating leukodystrophy (PMID: 29618326), and has been identified in 0.001% (1/113722) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374831450). 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: 1029126) and has been interpreted as likely pathogenic by Baylor Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg808Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_supporting (Richards 2015).

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