rs587780420
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_002693.3(POLG):c.1235C>T(p.Pro412Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,380 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. P412Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250770Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135644
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461238Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 726928
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:3
Observed as heterozygous in a patient with multiple mtDNA deletions in muscle and spastic ataxic gait; a second variant in POLG was not identified and segregation studies were not reported (PMID: 28130605); Functional studies suggest this variant may be associated with reduced exonuclease activity and normal polymerase activity (PMID: 27987238); 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: 28944914, 27987238, WangAnni2023[article], 32613234, 35861376, 28130605) -
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POLG: PS4:Moderate, PP3 -
Progressive sclerosing poliodystrophy Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the POLG protein (p.Pro412Leu). This variant is present in population databases (rs587780420, gnomAD 0.02%). This missense change has been observed in individual(s) with late onset spastic–ataxic gait and multiple lipomas, Parkinson disease (PMID: 28130605, 32613234). ClinVar contains an entry for this variant (Variation ID: 129988). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 27987238). 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. -
This variant was found heterozygously in a patient with chronic fatigue syndrome. The variant is absent from gnomAD and not described before. The variant is predicted to be damaging. In summary and based on ACMG criteria PM2, PP3 we classify this variant as Variant of unknown significance. -
POLG-related disorder Uncertain:1
The POLG c.1235C>T variant is predicted to result in the amino acid substitution p.Pro412Leu. This variant was reported in an individual with spastic ataxic gait and multiple lipomas (Da Pozzo et al. 2017. PubMed ID: 28130605) and an individual with bipolar disorder (Kasahara et al. 2017. PubMed ID: 27987238). In vitro functional study showed that exonuclease activity of this variant was lower compared to control, while polymerase activity remained unchanged (Kasahara et al. 2017. PubMed ID: 27987238). This variant is reported in 0.033% of alleles in individuals of East Asian 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