15-89327004-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_002693.3(POLG):c.1493A>C(p.Lys498Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,614,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251488Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135920
GnomAD4 exome AF: 0.000217 AC: 317AN: 1461886Hom.: 2 Cov.: 34 AF XY: 0.000205 AC XY: 149AN XY: 727242
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: POLG c.1493A>C (p.Lys498Thr) results in a non-conservative amino acid change in 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 4.8e-05 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders, allowing no conclusion about variant significance. c.1493A>C has been reported in the literature in individuals affected with Alpers syndrome or Cerebellar Ataxia (Hikmat_2017, Coutelier_2018). 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: 29482223, 28471437, 28865037, 34690748). ClinVar contains an entry for this variant (Variation ID: 206597). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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not provided Uncertain:2
PP3, PM2_moderate, PM3_supporting -
Reported in a patient with Alpers syndrome who also harbors an likely disease-causing variant in the POLG gene (PMID: 28471437); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28865037, 28471437) -
Progressive sclerosing poliodystrophy Uncertain:2
This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 498 of the POLG protein (p.Lys498Thr). This variant is present in population databases (rs769637557, gnomAD 0.008%). This missense change has been observed in individual(s) with Alpers syndrome (PMID: 28471437). ClinVar contains an entry for this variant (Variation ID: 206597). 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. -
The NM_002693.2:c.1493A>C (NP_002684.1:p.Lys498Thr) [GRCH38: NC_000015.10:g.89327004T>G] variant in POLG gene is interpretated to be a Uncertain Significance 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). PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
Inborn genetic diseases Uncertain:1
Hikmat, 2017a; Hikmat, 2017b Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
POLG-related disorder Uncertain:1
The POLG c.1493A>C variant is predicted to result in the amino acid substitution p.Lys498Thr. This variant was reported with a second POLG variant in an individual with Alpers syndrome (Supp. Table 1 in Hikmat et al 2017. PubMed ID: 28865037). This variant is reported in 0.0093% 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at