rs551811489
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_002693.3(POLG):βc.2977C>Tβ(p.Arg993Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,613,030 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 (β β ).
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250286Hom.: 0 AF XY: 0.0000960 AC XY: 13AN XY: 135408
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1460714Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 726672
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Reported in an individual with onset of Parkinson disease at age 72 who also harbored two additional POLG variants, one of which was considered pathogenic (PMID: 24122062); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30941926, 32502631, 24122062) -
not specified Uncertain:1
Variant summary: POLG c.2977C>T (p.Arg993Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) 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 0.00011 in 250286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.2977C>T has been reported in the literature in at-least one individual affected with features of Parkinsons Disease (example, Ylonen_2013 cited in Hsieh_2019). 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: 30941926, 24122062). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
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
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Inborn genetic diseases Uncertain:1
The p.R993C variant (also known as c.2977C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2977. The arginine at codon 993 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in conjunction with two additional POLG vairants in an individual with parkinsonism without progressive external ophthalmoplegia (Hsieh PC et al. Brain Behav, 2019 May;9:e01281). 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. -
POLG-related disorder Uncertain:1
The POLG c.2977C>T variant is predicted to result in the amino acid substitution p.Arg993Cys. This variant was reported in an individual with late-onset Parkinson disease (YlΓΆnen et al 2013. PubMed ID: 24122062). This variant is reported in 0.069% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Progressive sclerosing poliodystrophy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 993 of the POLG protein (p.Arg993Cys). This variant is present in population databases (rs551811489, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 405570). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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