chr15-89330217-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_002693.3(POLG):c.719C>T(p.Ser240Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.719C>T | p.Ser240Leu | missense_variant | 3/23 | ENST00000268124.11 | NP_002684.1 | |
POLGARF | NM_001406557.1 | c.774C>T | p.Val258= | synonymous_variant | 3/23 | NP_001393486.1 | ||
POLG | NM_001126131.2 | c.719C>T | p.Ser240Leu | missense_variant | 3/23 | NP_001119603.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.719C>T | p.Ser240Leu | missense_variant | 3/23 | 1 | NM_002693.3 | ENSP00000268124 | P1 | |
POLGARF | ENST00000706918.1 | c.774C>T | p.Val258= | synonymous_variant | 2/2 | ENSP00000516626 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250472Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135624
GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461030Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 726856
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2024 | Identified in an 11 year-old patient with encephalopathy, seizures, posterior stroke and stroke-like episodes, migraines, muscle weakness, and hepatic failure; however, a second POLG variant was not identified and results of parental testing were not provided (PMID: 21880868); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21880868) - |
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 | Nov 17, 2021 | - - |
POLG-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2024 | The POLG c.719C>T variant is predicted to result in the amino acid substitution p.Ser240Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% 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. - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 240 of the POLG protein (p.Ser240Leu). This variant is present in population databases (rs369175235, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of POLG-related disease who lacked a second variant in POLG (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 206582). 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 not expected to disrupt POLG protein function with a negative 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