rs113994097
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3PP5BP4
The NM_002693(POLG):c.2243G>C(p.Trp748Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 152210 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W748C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693 missense
Scores
Clinical Significance
Conservation
Links
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2243G>C | p.Trp748Ser | missense_variant | 13/23 | ENST00000268124.11 | |
POLG | NM_001126131.2 | c.2243G>C | p.Trp748Ser | missense_variant | 13/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2243G>C | p.Trp748Ser | missense_variant | 13/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000742 AC: 113AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000971 AC: 244AN: 251290Hom.: 0 AF XY: 0.000987 AC XY: 134AN XY: 135828
GnomAD4 exome AF: 0.000730 AC: 1066AN: 1460716Hom.: 1 AF XY: 0.000736 AC XY: 535AN XY: 726750
ClinVar
Submissions by phenotype
not provided Pathogenic:13Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 30, 2021 | - - |
not provided, no assertion provided | phenotyping only | GenomeConnect, ClinGen | - | Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics Inc | Jun 24, 2020 | The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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, 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 | Eurofins Ntd Llc (ga) | Feb 02, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | Criteria applied: PS1, PM1, PP1, PP3, PP4, PS3, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Karolinska University Hospital, Karolinska University Hospital | Feb 15, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 15, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PerkinElmer Genomics | Dec 21, 2020 | - - |
Progressive sclerosing poliodystrophy Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 31, 2022 | This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 28, 2022 | - - |
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.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:26077851) (PMID:15477547). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:20153822). PS3 => Well-established functional studies show a deleterious effect (PMID:17088268). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 19, 2018 | - - |
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
POLG-Related Spectrum Disorders Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2018 | The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3. - |
Mitochondrial DNA depletion syndrome 4b Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Klinikum rechts der Isar | Jul 28, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 10, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4. - |
Mitochondrial disease Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Apr 07, 2017 | - - |
not provided, no assertion provided | literature only | GeneReviews | - | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 25, 2017 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2018 | The p.W748S pathogenic mutation (also known as c.2243G>C), located in coding exon 12 of the POLG gene, results from a G to C substitution at nucleotide position 2243. The tryptophan at codon 748 is replaced by serine, an amino acid with highly dissimilar properties. This variant is a well described founder mutation, accounting for up to 8% of disease causing alleles in the Finnish population. Additionally, this mutation has been described many times in the homozygous and compound heterozygous states in individuals with Alpers-Huttenlocher syndrome (AHS), SANDO, MEMSA, and other autosomal recessive POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, myopathy, tremors, cognitive decline, and hearing loss (Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83; Janssen W et al. Acta Neurol Belg, 2016 Mar;116:17-25; Uusimaa J et al. Epilepsia, 2008 Jun;49:1038-45; Henao AI et al. Neuroradiol J, 2016 Feb;29:46-8; Masingue M et al. Mitochondrion, 2018 Feb; Hikmat O et al. Int J Mol Sci, 2017 Aug;18:). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Spinocerebellar ataxia with epilepsy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at