Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
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 |