ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.803G>C (p.Gly268Ala) (rs61752784)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000177165 SCV000228997 likely benign not specified 2015-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000415771 SCV000242265 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The G268A variant was initially reported in two patients with autosomal recessive progressive external ophthalmoplegia (arPEO) who had multiple DNA deletions in muscle, and both patients had two identifiable POLG variants by sequencing (Di Fonzo et al., 2003). G268A has subsequently been identified in severalpatients with sporadic PEO, hepatocerebral syndrome, or other neurological symptoms suggestive of a mitochondrial disorder who did not have a second identified POLG pathogenic variant on the otherallele (Gonzalez-Vioque et al., 2006; Blok et al., 2009). Blok et al. (2009) concluded that it is unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentifiedpathogenic variant in POLG or another gene that was not detected by the testing methods. Tang et al. (2011) questioned the reported pathogenicity of G268A and reported that in their cohort G268A was present at high frequency; however, it was not found with another POLG pathogenic variant in any oftheir patients. The G268A variant is observed in 78/11562 (0.67%) alleles from individuals of Latino background, including multiple unrelated homozygous individuals in large population cohorts (Lek et al., 2016). The G268A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenicvariants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). Additionally, in silico analysis predicts the G268A variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, itis unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000233823 SCV000287674 benign Progressive sclerosing poliodystrophy 2020-12-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415771 SCV000493481 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000177165 SCV000596506 uncertain significance not specified 2016-09-20 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000415771 SCV000610284 likely benign not provided 2017-02-22 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000415771 SCV000614735 likely benign not provided 2020-06-09 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000415771 SCV000802094 uncertain significance not provided 2019-12-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715855 SCV000846687 likely benign Seizures 2020-01-22 criteria provided, single submitter clinical testing No disease association in small case-control study;Other strong data
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000233823 SCV000887103 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768291 SCV000898903 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 2017-10-02 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain.
Mendelics RCV000233823 SCV001139685 likely benign Progressive sclerosing poliodystrophy 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001121511 SCV001280136 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GenomeConnect, ClinGen RCV000709833 SCV000840162 not provided POLG-related disorders no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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