rs149099318
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_002693.3(POLG):c.3442C>T(p.Arg1148Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,614,028 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1148H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3442C>T | p.Arg1148Cys | missense_variant | 21/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2714C>T | 3_prime_UTR_variant | 21/23 | |||
POLG | NM_001126131.2 | c.3442C>T | p.Arg1148Cys | missense_variant | 21/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3442C>T | p.Arg1148Cys | missense_variant | 21/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251384Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135886
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461708Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727150
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33469851) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | POLG: PM2, PP3 - |
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;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 24, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2018 | The p.R1148C variant (also known as c.3442C>T), located in coding exon 20 of the POLG gene, results from a C to T substitution at nucleotide position 3442. The arginine at codon 1148 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1148 of the POLG protein (p.Arg1148Cys). This variant is present in population databases (rs149099318, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 33469851). ClinVar contains an entry for this variant (Variation ID: 458715). 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%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at