ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.3643+48A>G

gnomAD frequency: 0.01182  dbSNP: rs2307454
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV001526409 SCV001736747 uncertain significance Mitochondrial disease 2021-05-06 reviewed by expert panel curation The c.3643+48A>G variant in POLG is present in the databases ExAC at 0.003%, gnomAD at 0.004% (PM2; observed < 0.05% frequency). This variant has been observed in 15 homozygotes in gnomAD and 5 homozygotes in ExAC (BS2 criteria met). Computational prediction data limited and no Revel score provided. This variant has not been reported in the literature. In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, BS2.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758553 SCV000887287 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3643+48A>G (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89317328T>C] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
GeneDx RCV000832476 SCV000974231 likely benign not provided 2018-06-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Mendelics RCV002249458 SCV002516797 likely benign not specified 2022-05-04 criteria provided, single submitter clinical testing

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