Submissions for variant NM_002693.3(POLG):c.2109C>A (p.Ala703=)

gnomAD frequency: 0.00845  dbSNP: rs2307429

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000118012	SCV000171095	benign	not specified	2012-04-09	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	RCV000460792	SCV000556222	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313914	SCV000847933	benign	Inborn genetic diseases	2016-10-03	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	RCV000460792	SCV000887077	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2109C>A (NP_002684.1:p.Ala703=) [GRCH38: NC_000015.10:g.89323863G>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.
Illumina Laboratory Services, Illumina	RCV001121412	SCV001280022	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV002483198	SCV002795056	likely 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	2021-10-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004704866	SCV005213945	likely benign	not provided		criteria provided, single submitter	not provided
Genetic Services Laboratory, University of Chicago	RCV000118012	SCV000152330	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.