ClinVar Miner

Submissions for variant NM_007055.4(POLR3A):c.1771-7C>G

dbSNP: rs201314157
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522489 SCV000617835 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing In silico analysis suggests this variant may impact gene splicing. In the absence of additional RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28459997, 31940116, 32582862, 33559318, 33597727, 32860008, 32214227, 33098801, 34440436, 34284285, 33726816)
CeGaT Center for Human Genetics Tuebingen RCV000522489 SCV000692692 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000787963 SCV000926986 uncertain significance Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2019-01-30 criteria provided, single submitter clinical testing
MyeliNeuroGene Lab, McGill University Health Center Research Institute RCV000787963 SCV000987277 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome criteria provided, single submitter research
Institute of Human Genetics, Klinikum rechts der Isar RCV000787963 SCV001150222 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2018-11-05 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000787963 SCV001426544 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome criteria provided, single submitter clinical testing
Pathology and Clinical Laboratory Medicine,King Fahad Medical City RCV000787963 SCV001438871 uncertain significance Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000522489 SCV001447405 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Manipal Academy of Higher Education RCV001290309 SCV001478356 likely pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2019-05-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV000787963 SCV001521992 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2020-07-08 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000787963 SCV001571373 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2021-04-12 criteria provided, single submitter clinical testing
Invitae RCV000522489 SCV002247159 pathogenic not provided 2021-12-09 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201314157, gnomAD 0.02%). This variant has been observed in individuals with POLR3A-related conditions (PMID: 28459997, 31940116, 32214227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449556). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 28459997). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222542 SCV002500585 pathogenic Pol III-related leukodystrophy 2022-03-22 criteria provided, single submitter clinical testing Variant summary: POLR3A c.1771-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00011 in 251416 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in POLR3A causing Pol III-Related Leukodystrophy (0.00011 vs ND), allowing no conclusion about variant significance. c.1771-7C>G has been reported in the literature in multiple individuals affected with Pol III-Related Leukodystrophy. These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=8, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Section for Clinical Neurogenetics,University of Tübingen RCV000787963 SCV001156098 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2019-08-01 no assertion criteria provided research

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