ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.3286C>T (rs201732356)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188613 SCV000242236 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing The R1096C variant in the POLG gene has been reported previously in multiple patients with Alpers syndrome, a clinical presentation suggestive of POLG deficiency, or progressive external ophthalmoplegia (arPEO) and peripheral neuropathy, who were either homozygous for the R1096C variant (Mohamed et al., 2011; Wong et al, 2008; Tang et al., 2011; Ashley et al. 2008) or compound heterozygous for the R1096C variant and another pathogenic variant (Tang et al., 2011; Ashley et al., 2008; Lax et al., 2012).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188613 SCV000706348 pathogenic not provided 2017-02-08 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758420 SCV000887123 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3286C>T (NP_002684.1:p.Arg1096Cys) [GRCH38: NC_000015.10:g.89318737G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 ; 21305355 . 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.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000758420 SCV000891542 likely pathogenic Progressive sclerosing poliodystrophy 2017-12-30 criteria provided, single submitter curation
Fulgent Genetics,Fulgent Genetics RCV000762952 SCV000893384 likely pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000758420 SCV001391869 pathogenic Progressive sclerosing poliodystrophy 2020-01-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1096 of the POLG protein (p.Arg1096Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201732356, ExAC 0.01%). This variant has been observed as homozygous or compound heterozygous in individuals affected with autosomal recessive POLG-related disease (PMID: 21305355, 22189570, 28471437, 30167885, 24265579, 21880868). It has also been reported as a single variant in an individual with sporadic progressive external ophthalmoplegia (PMID: 12707443); however, the role of this variant in autosomal dominant disease is unclear. ClinVar contains an entry for this variant (Variation ID: 206556). This variant has been reported to affect POLG protein function (PMID: 23208208, 20185557). This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 19752458, 16621917), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000758420 SCV001524399 pathogenic Progressive sclerosing poliodystrophy 2020-07-09 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genomics, and Precision Dentistry Research Unit, Faculty of Dentistry, Chulalongkorn University RCV001263172 SCV001245409 pathogenic Childhood myocerebrohepatopathy spectrum no assertion criteria provided research The p.Arg1096Cys variant in POLG gene has been previously reported many times with autosomal recessive inheritance pattern. Homozygous mutation of this variant was reported in a Saudi child with Alpers-Huttenlocher syndrome (AHS) (Kentab, 2019). Other reports could be accessed in The POLG Pathogenicity Prediction Server (

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