Submissions for variant NM_002693.3(POLG):c.2207A>G (p.Asn736Ser)

gnomAD frequency: 0.00092  dbSNP: rs138457939

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000712791	SCV000242187	likely benign	not provided	2021-02-09	criteria provided, single submitter	clinical testing	Reported in a female patient with recurrent major depression, ataxia, and cardiomyopathy (Verhoeven et al., 2011); however, the variant was found more frequent in population databases than would be expected based on the frequency of disease, calling into question the pathogenicity of this variant (Andreasen et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 21654874, 21880868, 31996268)
Genetic Services Laboratory, University of Chicago	RCV000188567	SCV000248556	uncertain significance	not specified	2014-04-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231376	SCV000287667	likely benign	Progressive sclerosing poliodystrophy	2025-01-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515256	SCV000611502	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	2017-05-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000712791	SCV000700969	uncertain significance	not provided	2018-04-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712791	SCV000843320	uncertain significance	not provided	2023-09-01	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). In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools disagree on the variant's effect on normal protein function.
Ambry Genetics	RCV002314741	SCV000847525	uncertain significance	Inborn genetic diseases	2023-09-27	criteria provided, single submitter	clinical testing	Unlikely to be causative of autosomal dominant progressive external ophthalmoplegia (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000231376	SCV000887295	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2207A>G (NP_002684.1:p.Asn736Ser) [GRCH38: NC_000015.10:g.89323462T>C] 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	RCV001119421	SCV001277820	uncertain significance	POLG-Related Spectrum Disorders	2017-04-28	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.
CeGaT Center for Human Genetics Tuebingen	RCV000712791	SCV001961533	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000188567	SCV002600811	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2207A>G (p.Asn736Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251376 control chromosomes, including 1 homozygote (gnomAD). c.2207A>G has been reported in the literature in heterozygous individuals affected with Progressive external ophthalmoplegia (Bychkov_2021), and depression, ataxia and cardiomyopathy (Verhoeven_2011). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33486010, 21654874). ClinVar contains an entry for this variant (Variation ID: 206516). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000712791	SCV005411126	uncertain significance	not provided	2024-01-24	criteria provided, single submitter	clinical testing	BS2
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252353	SCV001428105	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000712791	SCV001743172	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000712791	SCV001966286	uncertain significance	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002227937	SCV002507281	likely pathogenic	Tip-toe gait		flagged submission	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.
PreventionGenetics, part of Exact Sciences	RCV003985754	SCV004731597	likely benign	POLG-related disorder	2022-04-12	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).