Submissions for variant NM_002693.3(POLG):c.678G>C (p.Gln226His)

gnomAD frequency: 0.00056  dbSNP: rs147282197

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000710188	SCV000242262	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18156159, 21880868, 33600046)
Athena Diagnostics	RCV000710188	SCV000614733	uncertain significance	not provided	2021-10-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000710188	SCV000709292	uncertain significance	not provided	2018-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633538	SCV000754784	likely benign	Progressive sclerosing poliodystrophy	2024-01-26	criteria provided, single submitter	clinical testing
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 Laboratory Services, 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.
Institute of Human Genetics, Cologne University	RCV001263148	SCV001441226	uncertain significance	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2024-01-30	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000710188	SCV001961537	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	POLG: BP4
Centogene AG - the Rare Disease Company	RCV001808471	SCV002059496	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2019-06-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000710188	SCV002541299	uncertain significance	not provided	2022-02-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362986	SCV002661810	uncertain significance	Inborn genetic diseases	2021-03-17	criteria provided, single submitter	clinical testing	The c.678G>C (p.Q226H) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 678, causing the glutamine (Q) at amino acid position 226 to be replaced by a histidine (H). The p.Q226H alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317141	SCV004020890	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: POLG c.678G>C (p.Gln226His) results in a non-conservative amino acid change located in the exonuclease domain (IPR041336) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 247722 control chromosomes (gnomAD). c.678G>C has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders, including parkinsonism (Montaut_2018) and adult-onset chronic progressive external ophthalmoplegia (Heighton_2019) without strong evidence for causality, and as a compound heterozygous genotype together with a pathogenic variant in an individual diagnosed with sensory ataxic neuropathy with mtDNA deletions (Keller_2021). These data do not allow any conclusion about variant significance. 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: 31521625, 33600046, 29913018). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant with conflicting assessments: VUS (n=9), likely benign (n=2), likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678826	SCV000805012	uncertain significance	Autism; Seizure	2016-08-10	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000710188	SCV001742578	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000710188	SCV001931330	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710188	SCV001967299	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732768	SCV005346115	uncertain significance	POLG-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The POLG c.678G>C variant is predicted to result in the amino acid substitution p.Gln226His. This variant has been reported in the compound heterozygous state in an individual with infantile muscular atrophy and weakness (Keller et al. 2021. PubMed ID: 33600046). Additionally, this variant was reported in the heterozygous state in one patient with clinical features suggestive of POLG deficiency, although a second plausible causative variant was not identified (Tang et al. 2011. PubMed ID: 21880868, Supplementary Table 3). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.