Submissions for variant NM_002693.3(POLG):c.1550G>T (p.Gly517Val)

gnomAD frequency: 0.00516  dbSNP: rs61752783

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000118011	SCV000111915	benign	not specified	2014-09-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000118011	SCV000152329	likely benign	not specified	2019-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000118011	SCV000242169	benign	not specified	2016-05-25	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000223970	SCV000281444	likely benign	not provided	2016-05-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229511	SCV000287664	benign	Progressive sclerosing poliodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000223970	SCV000608735	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLG: BP4, BS2
Athena Diagnostics	RCV000223970	SCV000843315	benign	not provided	2017-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311532	SCV000846912	likely benign	Inborn genetic diseases	2018-07-02	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223970	SCV000884403	benign	not provided	2023-11-09	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000229511	SCV000887270	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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	RCV000768289	SCV000898901	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	2022-05-18	criteria provided, single submitter	clinical testing	POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related disease in the heterozygous, compound and double heterozygous state, many of which are reported with significantly variable phenotypes (Horvath 2006 PMID:16621917, Wong 2008 PMID:18546365, Tang 2011 PMID:21880868, Staropoli 2012 PMID:22727047, Gailey 2013 PMID:23808377, Woodbridge 2013 PMID:22647225, DaPozzo 2017 PMID:28130605). However, this variant is present in 0.7% (925/126620) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752783). This variant is present in ClinVar with multiple different classifications, including several Likely Benign/Benign entries (Variation ID:65665). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In addition, functional studies suggest that this variant retains 80-90% of activity relative to wild-type (Kasiviswanathan 2011 PMID:21856450). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is too conflicting for disease classification. Therefore, the clinical significance of this variant is uncertain.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118011	SCV000967286	likely benign	not specified	2018-10-05	criteria provided, single submitter	clinical testing	The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% (92 5/126620) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/), including 3 homozygotes. In addition, function al studies demonstrate an effect indistinguishable from wild type.
Mendelics	RCV000229511	SCV001139682	likely benign	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001117969	SCV001276215	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000229511	SCV001440547	uncertain significance	Progressive sclerosing poliodystrophy	2019-01-01	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001352901	SCV001547509	uncertain significance	Tip-toe gait	2021-02-04	criteria provided, single submitter	clinical testing	We conducted a clinical examination of patients about toe walking. The POLG c.1550G>T was detected in 2 patients. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847644	SCV002105553	benign	Hereditary spastic paraplegia	2021-01-22	criteria provided, single submitter	clinical testing
GeneReviews	RCV000055881	SCV000086887	not provided	Mitochondrial disease		no assertion provided	literature only
Department of Neurology, University Hospital of Strasbourg	RCV000186556	SCV000240098	pathogenic	Idiopathic camptocormia	2012-01-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000223970	SCV000802090	likely benign	not provided	2016-03-08	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000223970	SCV001741966	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000223970	SCV001927575	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000223970	SCV001969779	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985725	SCV004787329	benign	POLG-related disorder	2020-01-10	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).