Submissions for variant NM_002693.3(POLG):c.803G>C (p.Gly268Ala)

gnomAD frequency: 0.00364  dbSNP: rs61752784

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177165	SCV000228997	likely benign	not specified	2015-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000415771	SCV000242265	uncertain significance	not provided	2021-07-23	criteria provided, single submitter	clinical testing	Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentified pathogenic variant in POLG or another gene that was not detected by the testing methods (Blok et al., 2009; Tang et al. 2011); Pathogenicity of G268A was questioned as the G268A variant was present at high frequency in this cohort; however, it was not found with another POLG pathogenic variant in any of the patients (Tang et al., 2011); Functional studies are discordant regarding the effect of this variant; those studies using the yeast homologue demonstrate a deleterious effect, while those using human POLG demonstrate no significant effect (Baruffini et al., 2006; Baruffini et al., 2015; Macao et al., 2015; Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenic variants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database); This variant is associated with the following publications: (PMID: 14635118, 26095671, 25462018, 16940310, 26357557, 21880868, 19578034, 24508722, 16401742, 25118206, 27987238, 28128857, 29474836, 31139930, 30637288, 32391929, 34023347, 32949115)
Invitae	RCV000233823	SCV000287674	benign	Progressive sclerosing poliodystrophy	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000415771	SCV000493481	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	POLG: BS2
Genetic Services Laboratory, University of Chicago	RCV000177165	SCV000596506	uncertain significance	not specified	2016-09-20	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000415771	SCV000610284	likely benign	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000415771	SCV000614735	likely benign	not provided	2020-06-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000415771	SCV000802094	uncertain significance	not provided	2019-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312719	SCV000846687	likely benign	Inborn genetic diseases	2020-01-22	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	RCV000233823	SCV000887103	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768291	SCV000898903	uncertain significance	Progressive sclerosing poliodystrophy; 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	2021-11-11	criteria provided, single submitter	clinical testing	POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain.
Mendelics	RCV000233823	SCV001139685	likely benign	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121511	SCV001280136	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847817	SCV002104888	uncertain significance	Hereditary spastic paraplegia	2021-11-08	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV002516726	SCV003035490	uncertain significance	Charcot-Marie-Tooth disease axonal type 2U	2022-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000415771	SCV003809206	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177165	SCV004241129	likely benign	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain 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 0.004 in 1614062 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), suggesting that the variant is benign. c.803G>C has been reported in the literature in individuals affected with progressive external ophthalmoplegia in the homozygous state (DiFonzo_POLG_HM_2003, DelBo_2003) and in patients suggestive POLG deficiency (Tang_2015) as well as unspecified mitochondrial disorders (Cruz_2017). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. Experimental evidence involving the variant has been conflicting, with some yeast and cell transfection studies showing a damaging effect while other studies in human cells showed remaining functional activity (Baruffini_2006, Kasahara_2016, Baruffini_2015). The following publications have been ascertained in the context of this evaluation (PMID: 14635118, 16940310, 27987238, 21880868, 28128857, 25462018). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including 8 VUS, 8 likely benign/benign and 1 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000709833	SCV004738686	likely benign	POLG-related disorder	2021-04-15	criteria provided, single submitter	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).
GenomeConnect, ClinGen	RCV000709833	SCV000840162	not provided	POLG-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002227084	SCV002506570	likely pathogenic	Tip-toe gait	2021-10-01	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.