rs61752784
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2
The NM_002693.3(POLG):āc.803G>Cā(p.Gly268Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,062 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Benign. The variant received -8 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLG | NM_002693.3 | c.803G>C | p.Gly268Ala | missense_variant | Exon 3 of 23 | ENST00000268124.11 | NP_002684.1 | |
| POLG | NM_001126131.2 | c.803G>C | p.Gly268Ala | missense_variant | Exon 3 of 23 | NP_001119603.1 | ||
| POLGARF | NM_001430120.1 | c.*75G>C | downstream_gene_variant | NP_001417049.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLG | ENST00000268124.11 | c.803G>C | p.Gly268Ala | missense_variant | Exon 3 of 23 | 1 | NM_002693.3 | ENSP00000268124.5 | ||
| POLGARF | ENST00000706918.1 | c.*75G>C | downstream_gene_variant | ENSP00000516626.1 |
Frequencies
GnomAD3 genomes 0.00353 AC: 538AN: 152224Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00344 AC: 865AN: 251312 AF XY: 0.00348 show subpopulations
GnomAD4 exome AF: 0.00400 AC: 5843AN: 1461720Hom.: 17 Cov.: 32 AF XY: 0.00395 AC XY: 2871AN XY: 727180 show subpopulations
Age Distribution
GnomAD4 genome 0.00352 AC: 537AN: 152342Hom.: 1 Cov.: 32 AF XY: 0.00346 AC XY: 258AN XY: 74492 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:2
Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentified pathogenic variant in POLG or another gene that was not detected by the testing methods (Blok et al., 2009; Tang et al. 2011); Pathogenicity of G268A was questioned as the G268A variant was present at high frequency in this cohort; however, it was not found with another POLG pathogenic variant in any of the patients (Tang et al., 2011); Functional studies are discordant regarding the effect of this variant; those studies using the yeast homologue demonstrate a deleterious effect, while those using human POLG demonstrate no significant effect (Baruffini et al., 2006; Baruffini et al., 2015; Macao et al., 2015; Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenic variants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database); This variant is associated with the following publications: (PMID: 14635118, 26095671, 25462018, 16940310, 26357557, 21880868, 19578034, 24508722, 16401742, 25118206, 27987238, 28128857, 29474836, 31139930, 30637288, 32391929, 34023347, 32949115) -
- -
- -
- -
POLG: BS2 -
The POLG c.803G>C; p.Gly268Ala variant (rs61752784, ClinVar Variation ID: 196354) is reported in the literature in multiple individuals affected with PEO or other POLG-associated conditions (Di Fonzo 2003, Del Bo 2003, Gonzalez-Vioque 2006, Calejo 2018, Tang 2011, Hegarty 2021, Bar 2023). However, in many cases, an additional variant in POLG could not be identified, or other genetic findings could not be ruled out to contribute to the clinical presentation. This variant is found in the general population with an overall allele frequency of 0.34% (959/282684 alleles, including 4 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.967), though functional analyses indicate conflicting and mild reductions in protein function comparted to wild type POLG (Baruffini 2006 and Kasahara 2017). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Bar O et al. Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction. Front Neurol. 2023 May 5;14:1151835. PMID: 37234784 Baruffini E et al. Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. Hum Mol Genet. 2006 Oct 1;15(19):2846-55. PMID: 16940310. Calejo M et al. Late-onset Levodopa Responsive Parkinsonism Due to Polymerase ? 1 Mutations. Mov Disord Clin Pract. 2018 Oct 17;5(6):645-648. PMID: 30637288 Del Bo R et al. Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. Neurology. 2003 Oct 14;61(7):903-8. PMID: 14557557. Di Fonzo A et al. POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum Mutat. 2003 Dec;22(6):498-9. PMID: 14635118. Gonzalez-Vioque E et al. Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol. 2006 Jan;63(1):107-11. PMID: 16401742. Hegarty R et al. Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology. J Pediatr. 2021 Sep;236:124-130. PMID: 34023347. Kasahara T et al. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. Psychiatry Clin Neurosci. 2017 Aug;71(8):518-529. PMID: 27987238. Tang S et al. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet. 2011 Oct;48(10):669-81. PMID: 21880868. -
not specified Uncertain:1Benign:3
- -
- -
Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 1614062 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), suggesting that the variant is benign. c.803G>C has been reported in the literature in individuals affected with progressive external ophthalmoplegia in the homozygous state (DiFonzo_POLG_HM_2003, DelBo_2003) and in patients suggestive POLG deficiency (Tang_2015) as well as unspecified mitochondrial disorders (Cruz_2017). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. Experimental evidence involving the variant has been conflicting, with some yeast and cell transfection studies showing a damaging effect while other studies in human cells showed remaining functional activity (Baruffini_2006, Kasahara_2016, Baruffini_2015). The following publications have been ascertained in the context of this evaluation (PMID: 14635118, 16940310, 27987238, 21880868, 28128857, 25462018). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including 8 VUS, 8 likely benign/benign and 1 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -
- -
Progressive sclerosing poliodystrophy Benign:3
- -
The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . 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. -
- -
POLG-related disorder Benign:1Other:1
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). -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Tip-toe gait Pathogenic:1
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. -
POLG-Related Spectrum Disorders Uncertain:1
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. -
Hereditary spastic paraplegia Uncertain:1
- -
Charcot-Marie-Tooth disease axonal type 2U Uncertain:1
- -
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1
POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain -
Inborn genetic diseases Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at