ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.678G>C (p.Gln226His) (rs147282197)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000710188 SCV000242262 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing The Q226H variant has been reported previously in an individual with a clinical presentation suggestive of POLG deficiency; however, additional clinical information was not provided and information regarding parental testing was not available (Tang et al., 2011). The Q226H variant is observed in 94/124870 (0.1%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The Q226H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics Inc RCV000710188 SCV000614733 uncertain significance not provided 2019-04-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000710188 SCV000709292 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing
Invitae RCV000633538 SCV000754784 uncertain significance Progressive sclerosing poliodystrophy 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 226 of the POLG protein (p.Gln226His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs147282197, ExAC 0.07%). This variant has been reported in the heterozygous state in an individual affected with POLG deficiency (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 206581). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633538 SCV000887199 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.678G>C (NP_002684.1:p.Gln226His) [GRCH38: NC_000015.10:g.89330258C>G] 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. 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 Likely Benign.
Illumina Clinical Services Laboratory,Illumina RCV001121513 SCV001280138 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678826 SCV000805012 uncertain significance Seizures; Autism 2016-08-10 no assertion criteria provided clinical testing

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