ClinVar Miner

Submissions for variant NM_007215.4(POLG2):c.1352G>A (p.Gly451Glu)

dbSNP: rs104894632
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330384 SCV004039194 likely pathogenic POLG2-related disorder 2023-08-23 criteria provided, single submitter clinical testing Variant summary: POLG2 c.1352G>A (p.Gly451Glu) results in a non-conservative amino acid change located in the Anticodon-binding domain (IPR004154) and C-terminal domain (IPR042064) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251208 control chromosomes (gnomAD). c.1352G>A has been reported in the literature in at least one heterozygous individual affected with late-onset autosomal-dominant progressive external ophthalmoplegia with a positive family history of disease (e.g., Longley_2006). These data suggest the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant displays a severe defect in its ability to physically associate with the catalytic subunit and is thus unable to enhance processivity of the holoenzyme (e.g., Longley_2006, Chan_2009, Young_2011). Experimental studies also found that the variant displayed a dominant negative effect, leading to loss of homodimeric polymerase gamma acitivty and substantial impairment of heterodimeric activity in complex with the wild-type (Young_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19513667, 16685652, 21138766, 21555342, 26123486). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000005594 SCV000025776 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 2006-06-01 no assertion criteria provided literature only

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