Submissions for variant NM_002693.3(POLG):c.578G>A (p.Arg193Gln)

gnomAD frequency: 0.00071  dbSNP: rs3176162

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000020482	SCV001994834	uncertain significance	Mitochondrial disease	2021-05-07	reviewed by expert panel	curation	The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It is also seen in the homozygous state in 1 individual in gnomAD (BS2). This variant is not reported in the literature and no computational data is available. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2.
Eurofins Ntd Llc (ga)	RCV000724388	SCV000227268	uncertain significance	not provided	2017-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000724388	SCV000242161	likely benign	not provided	2021-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25462018)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541557	SCV000630159	likely benign	Progressive sclerosing poliodystrophy	2025-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313715	SCV000848541	uncertain significance	Inborn genetic diseases	2019-01-30	criteria provided, single submitter	clinical testing	The p.R193Q variant (also known as c.578G>A), located in coding exon 1 of the POLG gene, results from a G to A substitution at nucleotide position 578. The arginine at codon 193 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000541557	SCV000887102	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.578G>A (NP_002684.1:p.Arg193Gln) [GRCH38: NC_000015.10:g.89333177C>T] variant in POLG gene is interpretated to be a Likely 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). 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 Likely Benign.
Illumina Laboratory Services, Illumina	RCV001121514	SCV001280139	uncertain significance	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Athena Diagnostics	RCV000724388	SCV001474649	uncertain significance	not provided	2023-10-21	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental analysis yielded inconclusive results regarding the impact of this variant on protein function. The effect of variant in mtDNA mutability was shown to be neutral in a yeast model (PMID 25462018). However, this has not been studied in a mammalian model system.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724388	SCV002541300	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476997	SCV002779724	uncertain significance	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	2021-11-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724388	SCV005051155	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985723	SCV004723947	likely benign	POLG-related disorder	2023-08-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).