ClinVar Genomic variation as it relates to human health

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.

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)

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.

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.

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.

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.

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.

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).