ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2542G>A (p.Gly848Ser) (rs113994098)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000717974 SCV000848835 pathogenic Seizures 2017-01-27 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000188580 SCV000614716 pathogenic not provided 2016-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188580 SCV000892141 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188580 SCV000511422 pathogenic not provided 2017-01-05 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000014451 SCV000236513 pathogenic Progressive sclerosing poliodystrophy 2014-06-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188580 SCV000331837 pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515163 SCV000611298 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-05-18 criteria provided, single submitter clinical testing
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678386 SCV000804455 pathogenic Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1 2017-09-07 criteria provided, single submitter provider interpretation This 7 year old female with autism spectrum disorder was found to carry a paternally inherited missense variant in the POLG gene. Neither she nor her father have any of the features of autosomal dominant POLG-Related Disorder, but it is possible that features have not yet emerged. Metabolic testing has thus far been normal for the patient. The p.G848S variant is a commonly reported pathogenic variant in the POLG gene, representing approximately 10% of disease-causing variants in this gene (Tang et al., 2011). The p.G848S variant was initially identified in a patient with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in individuals with Alpers syndrome, Leigh syndrome, SANDO, and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Lamantea et al., 2002). This variant alters a highly conserved position in the polymerase domain of POLG, and functional studies indicate that it significantly impairs the enzyme's polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009).
GeneDx RCV000188580 SCV000242202 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing The G848S variant is a commonly reported pathogenic variant in the POLG gene, representing approximately 10% of disease-causing variants in this gene (Tang et al., 2011). The G848S variant was initially identified in a patient with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in individuals with Alpers syndrome, Leigh syndrome, SANDO, and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Lamantea et al., 2002). This variant alters a highly conserved position in the polymerase domain of POLG, and functional studies indicate that it significantly impairs the enzyme's polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009). Consistent with its high prevalence in POLG-related disorders, the G848S variant is observed in 43/126,688 alleles (0.034%) from individuals of non-Finnish European background and 49/277,176 total alleles (0.018%) in large population cohorts, and was not observed in the homozygous state in any control individuals within these populations (Lek et al., 2016). We interpret G848S as a pathogenic variant.
GeneReviews RCV000014449 SCV000040910 pathologic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect, ClinGen RCV000509449 SCV000607021 not provided POLG- Related Disorder no assertion provided phenotyping only 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.
Illumina Clinical Services Laboratory,Illumina RCV000363602 SCV000394274 pathogenic POLG-Related Spectrum Disorders 2017-08-28 criteria provided, single submitter clinical testing The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen et al. 2014). Haplotype analysis suggests it is most likely derived from a single ancient ancestor of European origin (Hakonen et al. 2007). The p.Gly848Ser variant has been reported in association with varied autosomal recessive phenotypes, but not in association with autosomal dominant POLG-related disorders. Across a selection of the available literature, the p.Gly848Ser variant is reported in a homozygous state in one individual with seizures who died suddenly at age five, and in a compound heterozygous state in three individuals with autosomal recessive progressive external ophthalmoplegia, two individuals with sensory ataxia neuropathy dysarthria and ophthalmoplegia, two individuals with Alpers syndrome and one individual with intractable epilepsy (Lamantea et al. 2002; Weiss et al. 2010; Milone et al. 2011; Gáti et al. 2011; Tang et al. 2011; Lax et al. 2012; Scalais et al. 2012; Uusimaa et al. 2013; Simon et al. 2014). It was also identified in one individual with progressive external ophthalmoplegia in a double heterozygous state along with a missense variant in the C10orf2 gene (Van Goethem et al. 2003). The p.Gly848Ser variant has also been identified in three unaffected heterozygous individuals (Lamantea et al. 2002). Segregation analysis in multiple families showed the p.Gly848Ser variant segregated with POLG-related disorders. The variant is absent from 200 control individuals and from 180 control chromosomes (Lamantea et al. 2002; Van Goethem et al. 2003; Tang et al. 2011) and is reported at a frequency of 0.00034 in the European (non-Finnish) population of the Genome Aggregation Database. Lamantea et al. (2002) note that the Gly848 residue is highly conserved, and functional studies by Kasiviswanathan et al. (2009) indicate that the p.Gly848Ser variant significantly impairs POLG activity and DNA binding affinity. Based on the collective evidence, the p.Gly848Ser variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000014451 SCV000543865 pathogenic Progressive sclerosing poliodystrophy 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 848 of the POLG protein (p.Gly848Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs113994098, ExAC 0.03%). This variant has been reported in several individuals affected with autosomal recessive progressive external ophthalmoplegia, Alpers syndrome, sensory ataxic neuropathy, dysarthria/ dysphagia and external ophthalmoplegia, Leigh syndrome, and other POLG-related disorders causing epilepsy, sensory neuronopathy, and optic atrophy (PMID: 18500570, 12872260, 22616202, 22006280, 22342071, 21670405, 22189570). This variant is considered a common cause of POLG-related disorders accounting for 10% of the mutations (PMID: 21880868, 17426723). ClinVar contains an entry for this variant (Variation ID: 13502). Experimental studies have shown that this missense change severely impairs the binding and enzyme activity of the POLG protein (PMID: 19478085, 17980715). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014449 SCV000034699 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2009-03-24 no assertion criteria provided literature only
OMIM RCV000014450 SCV000034700 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic 2009-03-24 no assertion criteria provided literature only
OMIM RCV000014451 SCV000034701 pathogenic Progressive sclerosing poliodystrophy 2009-03-24 no assertion criteria provided literature only
OMIM RCV000014452 SCV000034702 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2009-03-24 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000014451 SCV000803530 pathogenic Progressive sclerosing poliodystrophy 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Mitochondrial DNA depletion syndrome 4A (Alpers type), 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. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Common mutation frequently observed in multiple unrelated patients. (PMID:17426723,21880868). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19478085). PS3 => Well-established functional studies show a deleterious effect (PMID:19478085).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000014451 SCV000887116 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2542G>A (NP_002684.1:p.Gly848Ser) [GRCH38: NC_000015.10:g.89321792C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12210792 ; 16177225 . 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.

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