ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.32G>A (rs765472726)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724132 SCV000227273 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000724132 SCV000242213 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing The G11D variant has also been observed in individuals with POLG-related disorders but typically reported to occur on the same chromosome (in cis) with R852C with a pathogenic variant on the other allele (for examples, see Ashley et al., 2009; Tang et al., 2011, Human DNA Polymerase Gamma Mutation Database). In one such observation, authors concluded that G11D was likely a non-pathogenic polymorphism that may serve as a modifier variant (Stewart et al., 2009). The G11D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, it alters a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc RCV000724132 SCV000614723 uncertain significance not provided 2019-06-11 criteria provided, single submitter clinical testing
Invitae RCV000633544 SCV000754790 uncertain significance Progressive sclerosing poliodystrophy 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 11 of the POLG protein (p.Gly11Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs765472726, ExAC 0.4%). This variant has been observed in several individuals affected with POLG-related disorders. However, in most cases it is reported on the same chromosome (cis) with another pathogenic variant (p.Arg852Cys) (PMID: 19251978, 18487244, 21880868, 22494076). ClinVar contains an entry for this variant (Variation ID: 195182). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633544 SCV000886985 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.32G>A (NP_002684.1:p.Gly11Asp) [GRCH38: NC_000015.10:g.89333723C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . 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. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Fulgent Genetics,Fulgent Genetics RCV000763999 SCV000894950 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001116627 SCV001274737 uncertain significance POLG-Related Spectrum Disorders 2017-04-28 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252351 SCV001428103 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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