ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2420G>A (p.Arg807His) (rs796052887)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188575 SCV000242197 pathogenic not provided 2014-01-18 criteria provided, single submitter clinical testing p.Arg807His (CGT>CAT): c.2420 G>A in exon 14 of the POLG gene (NM_002693.2). The R807H missense mutation in the POLG gene has been reported previously in a one-year-old patient with Alpers syndrome who was compound heterozygous for R807H and another POLG mutation (Tang et al., 2011). Other mutations at this position in the POLG gene (R807C, R807P) have also been reported as pathogenic. The variant is found in MITONUC-MITOP panel(s).
Invitae RCV000758305 SCV000939963 pathogenic Progressive sclerosing poliodystrophy 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 807 of the POLG protein (p.Arg807His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Alpers-Huttenlocher syndrome; in at least one of these individuals it was found on the opposite chromosome (in trans) from a pathogenic variant (PMID: 21880868, 29302508). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 206523). 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 and their clinical significance is uncertain. This variant disrupts the p.Arg807 amino acid residue in POLG. Other variants that disrupt this residue have been observed in affected individuals (PMID: 16919951, 21357833, 14635118), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758305 SCV000886962 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2420G>A (NP_002684.1:p.Arg807His) [GRCH38: NC_000015.10:g.89322748C>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. 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 Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.