ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1276G>A (p.Gly426Ser) (rs775576189)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763997 SCV000894948 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, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000534104 SCV000630090 uncertain significance Progressive sclerosing poliodystrophy 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 426 of the POLG protein (p.Gly426Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs775576189, ExAC 0.002%). This variant has been reported in the heterozygous state in 3 siblings affected with epilepsy, cerebellar ataxia, and/or juvenile cataracts, as well as in an unaffected sibling (PMID: 19578034). This variant has also been reported in the compound heterozygous state in an individual affected with seizures but without detectable mtDNA copy number depletion (PMID: 21880868). 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 disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that has been reported in affected and unaffected individuals and that has uncertain impact on RNA splicing and protein function. Without additional genetic and/or functional data, the clinical significance of this variant is not known. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000534104 SCV000887142 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1276G>A (NP_002684.1:p.Gly426Ser) [GRCH38: NC_000015.10:g.89327324C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.

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