ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3287G>A (p.Arg1096His) (rs368435864)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188614 SCV000242237 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing The Arg1096His missense variants in the POLG gene was previously reported in a patient with a clinical diagnosis of Alpers syndrome who had a second POLG variant on the other chromosome (Horvath et al., 2006). A different amino acid substitution at the same position, Arg1096Cys, is a common POLG variant that has been identified in multiple patients with autosomal recessive POLG-related disorders (Tang et al., 2011). Although Arg1096His is a conservative amino acid substitution, it alters a highly conserved position in the polymerase domain of the protein, and mulitiple in silico algorithms predict Arg1096His is damaging to protein structure/function.
Invitae RCV000551933 SCV000630143 likely pathogenic Progressive sclerosing poliodystrophy 2019-07-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1096 of the POLG protein (p.Arg1096His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs368435864, ExAC 0.01%). This variant has been observed in individuals affected with autosomal recessive Alpers syndrome or progressive external ophthalmoplegia (PMID: 16621917, 19752458). ClinVar contains an entry for this variant (Variation ID: 206557). Experimental studies have shown that this missense change significantly decreases POLG nucleotide incorporation efficiency and leads to mtDNA depletion (PMID: 23208208, 20185557). A different missense substitution at this codon (p.Arg1096Cys) has been determined to be pathogenic (PMID: 21880868, 22189570, 21305355, 24265579, 12707443, 23545419). This suggests that the arginine residue is critical for POLG protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in affected individuals and has been found to impact POLG function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188614 SCV000706349 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000718125 SCV000848987 likely pathogenic Seizures 2017-02-10 criteria provided, single submitter clinical testing The p.R1096H variant (also known as c.3287G>A), located in coding exon 20 of the POLG gene, results from a G to A substitution at nucleotide position 3287. The arginine at codon 1096 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this alteration's yeast equivalent was found to cause high mytocondrial dysfunction and decreased polymerase activity leading to mtDNA depletion (Stumpf JD et al. Hum. Mol. Genet., 2010 Jun;19:2123-33). In another functional study, this alteration showed decreased affinity for the DNA substrate and decreased rate of nucleotide incorporation, but increased affinity for the incoming nucleotide (Sohl CD et al. Hum. Mol. Genet., 2013 Mar;22:1074-85). In addition, this alteration has been detected in conjunction with POLG p.R627Q in several individuals with phenotypes including: Alpers syndrome, progressive external ophthalmoplegia (PEO), focal nocturnal motor epilepsy with status epilepticus at one month postpartum, and early-onset cerebellar ataxia with PEO; however, phase was not determined in any of these individuals (Horvath R et al. Brain, 2006 Jul;129:1674-84; Schulte C et al. Neurology, 2009 Sep;73:898-900; Savard M et al. Neurology, 2013 Aug;81:770-1; Schicks J et al. Mov. Disord., 2010 Nov;25:2678-82).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. ​ ​
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000551933 SCV000887124 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3287G>A (NP_002684.1:p.Arg1096His) [GRCH38: NC_000015.10:g.89318736C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. 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. 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 Pathogenic.

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