Submissions for variant NM_002693.3(POLG):c.1984G>A (p.Glu662Lys)

gnomAD frequency: 0.00547  dbSNP: rs2307450

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000020474	SCV001994835	benign	Mitochondrial disease	2021-05-07	reviewed by expert panel	curation	The c.1984G>A (p.Glu662Lys) variant in POLG has been reported with an allele frequency in the population databases: 0.9 % in gnomAD and in the Latino population at 7% (BA1). It is also seen in the homozygous state in 112 individuals in gnomAD and 42 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2.
Eurofins Ntd Llc (ga)	RCV000080022	SCV000111916	benign	not specified	2013-07-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000080022	SCV000171092	benign	not specified	2013-05-28	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224640	SCV000281339	benign	not provided	2015-05-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233567	SCV000287665	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000080022	SCV000309132	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000320624	SCV000394285	benign	POLG-Related Spectrum Disorders	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV002311517	SCV000846622	benign	Inborn genetic diseases	2016-05-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224640	SCV000885994	benign	not provided	2023-10-06	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000233567	SCV000887074	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1984G>A (NP_002684.1:p.Glu662Lys) [GRCH38: NC_000015.10:g.89324193C>T] variant in POLG gene is interpretated to be a 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). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847610	SCV002105560	benign	Hereditary spastic paraplegia	2020-03-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000224640	SCV005294882	benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000224640	SCV000802088	benign	not provided	2017-10-25	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224640	SCV001929188	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224640	SCV001970878	likely benign	not provided		no assertion criteria provided	clinical testing