Submissions for variant NM_002693.3(POLG):c.2254C>T (p.Leu752=)

gnomAD frequency: 0.01204  dbSNP: rs41564016

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001753495	SCV001994857	benign	Mitochondrial disease	2021-05-23	reviewed by expert panel	curation	The c.2254 C>T (p.Leu752=) variant in POLG has been reported with an allele frequency in the population at 1.3 % in GnomAD and 6.2% in ExAC (BS1). It is also a synonymous change which is not predicted to impact the protein (BP7). In summary, this variant meets criteria to be classified benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS1, BP7.
GeneDx	RCV000118013	SCV000171098	benign	not specified	2011-09-15	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.
PreventionGenetics, part of Exact Sciences	RCV000118013	SCV000309134	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275068	SCV000394278	likely benign	POLG-Related Spectrum Disorders	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464149	SCV000556231	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312229	SCV000846668	likely benign	Inborn genetic diseases	2016-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000464149	SCV000887078	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2254C>T (NP_002684.1:p.Leu752=) [GRCH38: NC_000015.10:g.89323415G>A] 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000676324	SCV001156801	benign	not provided	2023-10-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000118013	SCV001476788	benign	not specified	2024-04-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847710	SCV002105567	benign	Hereditary spastic paraplegia	2021-02-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000676324	SCV002497813	benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	POLG: BP4, BP7, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000676324	SCV005294879	benign	not provided		criteria provided, single submitter	not provided
Genetic Services Laboratory, University of Chicago	RCV000118013	SCV000152331	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	RCV000676324	SCV000802085	benign	not provided	2016-02-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000676324	SCV001742612	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000118013	SCV001931202	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000676324	SCV001973085	likely benign	not provided		no assertion criteria provided	clinical testing