Submissions for variant NM_002693.3(POLG):c.3572A>G (p.Lys1191Arg)

dbSNP: rs1567183988

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001759445	SCV001994854	uncertain significance	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3572 A>G (p.Lys1191Arg) variant in POLG is absent in population databases (PM2). Computational prediction tool Revel score 0.938 (PP3). This variant has been reported in trans with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) in a 1 year old who presented with Childhood myocerebrohepatopathy spectrum and pancreatisis (PM3_supporting; PMID: 18546365). There is a likely pathogenic variant at the same amino acid position p.Lys1191Asn seen in 3 cases as compound heterozygotes. Two cases with Ala467Thr presenting with Alpers syndrome and one with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM5_supporting; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, there is insufficient evidence to characterize this variant and therefore it remains a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3, PM5_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758331	SCV000886996	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3572A>G (NP_002684.1:p.Lys1191Arg) [GRCH38: NC_000015.10:g.89317447T>C] 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. PS2:This is a de Novo variant in POLG with confirmation of paternity & maternity 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. 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.