rs796052888
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_002693.3(POLG):c.2558G>A(p.Arg853Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2558G>A | p.Arg853Gln | missense_variant | 16/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1830G>A | 3_prime_UTR_variant | 16/23 | |||
POLG | NM_001126131.2 | c.2558G>A | p.Arg853Gln | missense_variant | 16/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2558G>A | p.Arg853Gln | missense_variant | 16/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251394Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 853 of the POLG protein (p.Arg853Gln). This variant is present in population databases (rs796052888, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive myocerebrohepatopathy (PMID: 18546365). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 19478085, 20185557). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | The NM_002693.2:c.2558G>A (NP_002684.1:p.Arg853Gln) [GRCH38: NC_000015.10:g.89321776C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 27, 2023 | ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 moderated, PM5 moderated, PP3 supporting - |
Mitochondrial DNA depletion syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2023 | Variant summary: POLG c.2558G>A (p.Arg853Gln) results in a conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.2558G>A has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with features of autosomal recessive POLG-Related Mitochondrial DNA Depletion Syndrome/POLG spectrum of disorders (example, Wong_2008, Li_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Kasiviswanathan_2009). The most pronounced variant effect results in <10% of normal Polymerase gamma enzyme activity in-vitro. The absence of significant polymerase activity displayed by the p.Arg853Gln polymerase gamma is consistent with mtDNA depletion in the patients and helps to explain the early childhood myocerebrohepatopathy (Wong_2008). The following publications have been ascertained in the context of this evaluation (PMID: 19478085, 34690748, 20185557, 26224072, 18546365). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2016 | p.Arg853Gln (CGG>CAG): c.2558 G>A in exon 16 of the POLG gene (NM_002693.2). The R853Q missense mutation in the POLG gene has been reported in a patient with myocerebrohepatopathy spectrum (MCHS) who was compound heterozygous for R853Q and two other missense mutations on the opposite POLG allele (Wong et al., 2008). R853Q is located in the thumb subdomain of the POLG protein and expression studies found that this mutation is associated with less than 1% residual polymerase gamma activity compared to wild type (Kasiviswanathan et al., 2009). Therefore, R853Q is considered a disease-causing mutation. The variant is found in EPILEPSY,MITONUC-MITOP panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at