ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2665G>A (p.Ala889Thr) (rs763393580)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518474 SCV000614717 pathogenic not provided 2019-02-14 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Statistically enriched in patients compared to ethnically matched controls.
Invitae RCV000695266 SCV000823754 uncertain significance Progressive sclerosing poliodystrophy 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 889 of the POLG protein (p.Ala889Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs763393580, ExAC 0.005%). This variant has been reported as homozygous and as compound heterozygous in individuals with progressive external ophthalmoplegia (PEO) (PMID: 24099403, 12975295). This variant has also been reported as occurring in cis with a polymorphism variant (p.Glu1143Gly) in a family with 2 brothers affected with PEO and neurological features; however, additional family members with these variants including the mother and 2 maternal uncles did not have PEO (PMID: 15800909). ClinVar contains an entry for this variant (Variation ID: 448104). Experimental studies have shown that this missense change (p.Ala889Thr) results in decreased cellular oxidative growth and reduced gap-filling DNA polymerase activity (PMID: 17980715, 25462018). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000518474 SCV001334803 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000844909 SCV000986716 not provided POLG-related disorders no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 06/02/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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.