Submissions for variant NM_002693.3(POLG):c.3451C>T (p.Leu1151=)

gnomAD frequency: 0.00004  dbSNP: rs769193603

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001753854	SCV001994838	uncertain significance	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3451C>T (p.L1151L) variant in POLG is present in population databases ExAC at 0.11% frequency and not observed in homozygotes (no criteria is met). There is limited computational predictions and the tool Revel unavailable given limited data. This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BP7
GeneDx	RCV000422598	SCV000514245	benign	not specified	2015-04-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758384	SCV000887059	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3451C>T (NP_002684.1:p.Leu1151=) [GRCH38: NC_000015.10:g.89318572G>A] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758384	SCV001001207	likely benign	Progressive sclerosing poliodystrophy	2023-12-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985780	SCV004752273	likely benign	POLG-related disorder	2019-07-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).