ClinVar Miner

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

dbSNP: rs201314157
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Total submissions: 22
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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 Munich, Klinikum Rechts Der Isar, Tu München 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, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India 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 2023-09-30 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.
Department of Biochemistry, Faculty of Medicine, University of Khartoum RCV000787963 SCV002573699 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome criteria provided, single submitter research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000787963 SCV003807344 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2022-12-23 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 supporting
Baylor Genetics RCV001290309 SCV003836126 pathogenic Neonatal pseudo-hydrocephalic progeroid syndrome 2022-01-20 criteria provided, single submitter clinical testing
3billion RCV000787963 SCV003842137 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). In silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.04). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 32582862). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000449556 / PMID: 28459997). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) RCV003387867 SCV003920804 pathogenic POLR3A-related disorders 2023-04-27 criteria provided, single submitter research
Preventiongenetics, part of Exact Sciences RCV003409747 SCV004113028 likely pathogenic POLR3A-related condition 2022-08-29 criteria provided, single submitter clinical testing The POLR3A c.1771-7C>G variant is predicted to interfere with splicing. The variant is predicted to weaken the acceptor splice site based on available prediction programs (Alamut Visual v2.10). This variant has been reported in the homozygous state in multiple unrelated individuals with spastic ataxia (Minnerop et al. 2017. PubMed ID: 28459997). This variant has also been observed in the compound heterozygous state in multiple unrelated individuals with POLR3A-related leukodystrophy and movement disorder (Harting et al. 2020. PubMed ID: 31940116; Perrier et al. 2020. PubMed ID: 32582862). Analysis of cDNA derived from affected individuals who were homozygous for the c.1771-7C>G variant showed the presence of both wild-type transcript and two abnormal transcripts, either lacking exon 14 or lacking both exons 13 and 14 (Minnerop et al. 2017. PubMed ID: 28459997). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-79769440-G-C). This variant is interpreted as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000787963 SCV004232688 pathogenic Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome 2024-01-24 criteria provided, single submitter curation The c.1771-7C>G variant in POLR3A has been reported in >10 individuals with POLR3A-related disorders (PMID: 28459997, 32214227, 31940116, 32582862, 33098801, 34440436, 32860008, 34234304, 33726816, 34284285, 33559318), segregated with disease in 3 affected relatives from 3 families (PMID: 28459997, 32582862), and has been identified in 0.01% (6/35434) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201314157). 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#: 449556) and has been interpreted as likely pathogenic or pathogenic by multiple laboratories. Of the many affected individuals, 5 of those were homozygotes, and at least 3 were compound heterozygotes that carried reported pathogenic and likely pathogenic variants in trans, which increases the likelihood that the c.1771-7C>G variant is pathogenic (VariationID: 684773, 430255, 684772; PMID: 28459997, 32214227, 31940116, 32582862, 33098801, 34440436, 32860008). In vitro functional studies provide some evidence that the c.1771-7C>G variant may impact protein function (PMID: 28459997, 32582862). However, these types of assays may not accurately represent biological function. This variant is located in the 5’ splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PS3_moderate, PM3_very-strong, PP1_moderate (Richards 2015).
Revvity Omics, Revvity Omics RCV000522489 SCV004238111 pathogenic not provided 2023-11-20 criteria provided, single submitter clinical testing
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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