ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2021G>A (p.Gly674Asp) (rs200257554)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001721213 SCV000242124 likely benign not provided 2020-12-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26557169)
Invitae RCV000633561 SCV000754807 likely benign Progressive sclerosing poliodystrophy 2020-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720525 SCV000851403 uncertain significance Seizures 2017-12-15 criteria provided, single submitter clinical testing The p.G674D variant (also known as c.2021G>A), located in coding exon 10 of the POLG gene, results from a G to A substitution at nucleotide position 2021. The glycine at codon 674 is replaced by aspartic acid, an amino acid with similar properties. This alteration was detected in an individual with paroxysmal exertion induced dystonia (PED) and early onset exertion induced dystonia in conjunction with a second POLG alteration of unknown significance (c.3644-­27T>G). The p.G674D alteration was also detected in the individual's father. Both the proband and his father also carried the SURF1 c.237G>T alteration which authors considered to be pathogenic; therefore, it is unknown which alteration(s) is causative (Chandra SR et al. J Pediatr Neurosci;10:254-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188510 SCV000861137 likely benign not specified 2018-05-07 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633561 SCV000887292 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2021G>A (NP_002684.1:p.Gly674Asp) [GRCH38: NC_000015.10:g.89324156C>T] variant in POLG gene is interpretated to be a Likely 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). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768054 SCV000898899 uncertain significance Progressive sclerosing poliodystrophy; Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-10-13 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 11 p.Gly674Asp (c.2021G>A): This variant has not been reported in the literature but is present in 0.1% (55/30782) of South Asian individuals in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:206462). This variant Aspartic Acid (Asp) is present in >5 species (including mammals) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV001121414 SCV001280024 uncertain significance POLG-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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