15-89321007-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_002693.3(POLG):āc.2740A>Cā(p.Thr914Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,614,050 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T914A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2740A>C | p.Thr914Pro | missense_variant | 18/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2012A>C | 3_prime_UTR_variant | 18/23 | |||
POLG | NM_001126131.2 | c.2740A>C | p.Thr914Pro | missense_variant | 18/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2740A>C | p.Thr914Pro | missense_variant | 18/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000112 AC: 28AN: 250820Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135632
GnomAD4 exome AF: 0.000199 AC: 291AN: 1461814Hom.: 0 Cov.: 35 AF XY: 0.000190 AC XY: 138AN XY: 727208
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2022 | Accounts for approximately 3% of disease-causing alleles and has been identified in patients with autosomal recessive POLG-related disorders, including Alpers syndrome and mitochondrial spinocerebellar ataxia and epilepsy (MSCAE) (Wong et al. 2008; Horvath et al. 2006; Taanman et al. 2009; Hinnell et al. 2012); Published functional studies demonstrate a damaging effect (Roos et al., 2013); 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: 16545482, 24642831, 20138553, 18487244, 30021052, 32042919, 23446635, 18828154, 16621917, 21357833, 18546365, 21956653, 16639411, 19578034, 23084792, 23446645, 21282586, 20843780, 27450679, 28471437, 30167885, 31425757, 25160553, 23921535, 21880868, 31980526) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 09, 2023 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with autosomal recessive POLG-related disorders and appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study shows this variant impairs DNA binding affinity and DNA polymerase activity compared to wild-type (PMID: 23446635). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 05, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 07, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Progressive sclerosing poliodystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | The NM_002693.2:c.2740A>C (NP_002684.1:p.Thr914Pro) [GRCH38: NC_000015.10:g.89321007T>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 914 of the POLG protein (p.Thr914Pro). This variant is present in population databases (rs139590686, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive adult onset progressive external ophthalmoplegia in a single family (PMID: 23446645). This variant has also been reported, along with a second, rare POLG variant in several individuals affected with a POLG-related disorder (PMID: 16621917, 21956653, 18487244, 21880868, 23921535, 20843780, 21357833, 21282586) including several individuals affected with Alpers syndrome (PMID: 16545482, 16639411, 18546365, 18828154, 23446635, 24642831, 27450679). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279961). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 18828154, 23446635). For these reasons, this variant has been classified as Pathogenic. - |
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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 18, 2021 | - - |
POLG-Related Spectrum Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | - - |
POLG-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The POLG c.2740A>C variant is predicted to result in the amino acid substitution p.Thr914Pro. This variant has been reported to be pathogenic for POLG-related disorders (Horvath et al. 2006. PubMed ID: 16621917; Wong et al. 2008. PubMed ID: 18546365; Tang et al. 2011. PubMed ID: 21880868; Hedberg-Oldfors et al. 2020. PubMed ID: 32042919). The majority of affected patients who carry this variant harbor a second pathogenic variant on the opposite allele (in trans), resulting in autosomal recessive disease. At least one patient, who presented with progressive external ophthalmoplegia (PEO), carried this variant in the heterozygous state alone (Wong et al. 2008. PubMed ID: 18546365). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89864238-T-G). This variant is interpreted as pathogenic. - |
Tip-toe gait Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Oct 01, 2021 | Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. - |
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at