Submissions for variant NM_002693.3(POLG):c.3597C>A (p.Thr1199=)

gnomAD frequency: 0.00770  dbSNP: rs2307443

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	RCV001526406	SCV001736744	benign	Mitochondrial disease	2021-05-06	reviewed by expert panel	curation	The c.3597C>A (p.T1199=) variant in POLG is present in population databases ExAC at 1.269 (BA1; observed > 1% frequency). Computational prediction tool Revel unavailable given limited data. This variant was observed in homozygotes in 17 cases in gnomAD and 5 case in ExAC (BS2). This variant is a coding synonymous change (BP7). In summary, there is sufficient evidence to characterized this variant as a benign for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1, BS2, BP7.
GeneDx	RCV000127547	SCV000171124	benign	not specified	2012-03-26	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231024	SCV000287673	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000127547	SCV000309147	benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000127547	SCV000614729	benign	not specified	2017-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312590	SCV000846573	benign	Inborn genetic diseases	2016-05-26	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000231024	SCV000887285	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3597C>A (NP_002684.1:p.Thr1199=) [GRCH38: NC_000015.10:g.89317422G>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. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Illumina Laboratory Services, Illumina	RCV001117760	SCV001275980	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847756	SCV002104878	benign	Hereditary spastic paraplegia	2021-06-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000676316	SCV002497808	benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	POLG: BP4, BP7, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000676316	SCV005294865	benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000676316	SCV000802074	benign	not provided	2016-02-19	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000676316	SCV001743427	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000127547	SCV001954420	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000127547	SCV001971346	benign	not specified		no assertion criteria provided	clinical testing