ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518474 SCV000614717 pathogenic not provided 2016-10-05 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.
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.

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