Submissions for variant NM_002693.3(POLG):c.3428A>G (p.Glu1143Gly)

gnomAD frequency: 0.02704  dbSNP: rs2307441

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000020476	SCV001736741	benign	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3428A>G (p.E1143G) variant in POLG has been reported 2.881 % in gnomAD (BA1). It is also seen in the homozygous state in 175 individuals in gnomAD and 65 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)	RCV000118018	SCV000203322	benign	not specified	2014-03-14	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000118018	SCV000257929	benign	not specified	2015-04-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118018	SCV000309143	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000386578	SCV000483523	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118018	SCV000540098	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 37/2178=1.6%
Invitae	RCV000469563	SCV000556246	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000676317	SCV000604901	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000676317	SCV000843333	benign	not provided	2018-07-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311518	SCV000846384	benign	Inborn genetic diseases	2016-03-21	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.
Fulgent Genetics, Fulgent Genetics	RCV000755650	SCV000883049	benign	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2021-08-03	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000469563	SCV000887280	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3428A>G (NP_002684.1:p.Glu1143Gly) [GRCH38: NC_000015.10:g.89318595T>C] 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). Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Illumina Laboratory Services, Illumina	RCV001119316	SCV001277698	likely benign	POLG-Related Spectrum Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000676317	SCV001936001	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17980715, 21686371, 25497598, 23448099, 17088268, 22166854, 23783014, 20691285, 20981092, 21228398, 15477547, 27884173, 26104464, 26468652, 18991199, 24122062, 30255931, 25925909, 25462018, 33469851)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847611	SCV002105584	benign	Hereditary spastic paraplegia	2021-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000118018	SCV002766201	benign	not specified	2022-11-29	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3428A>G (p.Glu1143Gly) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.029 in 251414 control chromosomes in the gnomAD database, including 156 homozygotes, strongly suggesting that the variant is benign. c.3428A>G has been reported in the literature in cis with a pathogenic variant in individuals affected with POLG-Related Spectrum Disorders, indicating that it is likely benign and not the cause of the disease phenotype (e.g. Ferrari_2005, Horvath_2006). At least one publication reports experimental evidence evaluating an impact on protein function and the results showed no damaging effect of this variant on polymerase activity (e.g. Chan_2006). Thirteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All classified the variant as either benign (n= 9) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000118018	SCV000152336	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676317	SCV000802076	likely benign	not provided	2016-02-25	no assertion criteria provided	clinical testing
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV000999632	SCV001156346	not provided	Association with valproate-induced liver toxicity		no assertion provided	phenotyping only	Variant interpreted as Risk factor and reported on 09-22-2017 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000676317	SCV001743070	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000118018	SCV001807291	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000118018	SCV001930440	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000676317	SCV001958733	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118018	SCV001968485	benign	not specified		no assertion criteria provided	clinical testing