ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2209G>C (p.Gly737Arg) (rs121918054)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188568 SCV000225831 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000188568 SCV000242188 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The G737R pathogenic variant in the POLG gene has been reported in the presence of a second POLG variant in association with diverse clinical presentations of autosomal recessive POLG-related disorders that lead to early-onset parkinsonism, progressive external opthalmoplegia, sensory peripheral neuropathy, seizures, ataxia, hearing loss, myocerebrohepatopathy, and Charcot-Marie-Tooth disease (Davidzon et al., 2006; Horvath et al., 2006; Wong et al., 2008; Tzoulis et al., 2009; Tang et al., 2011; Rempe et al., 2016). While not seen in the homozygous state, the G737R variant is observed in 162/126,642 (0.1%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The G737R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret G737R as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000370280 SCV000245652 likely pathogenic POLG-Related Spectrum Disorders 2016-12-23 criteria provided, single submitter clinical testing The p.Gly737Arg (NM_002693.2 c.2209G>C) variant in POLG has been reported in 10 compound heterozygous individuals presenting with POLG-related mitochondrial DNA (mtDNA) depletion syndromes (Horvath 2006, Davidzon 2006, Wong 2008, Harrower 2 008, Tzoulis 2009, Tang 2011). This variant has been identified in 0.1% (67/6651 4) of European chromosomes in ExAC though this frequency in consistent with a re cessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p. Gly737Arg variant is likely pathogenic for POLG-related mitochondrial DNA (mtDNA) depletion syndromes in an autosomal recessive manner based upon biallelic case observations and consisten t allele frequency.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188568 SCV000280606 pathogenic not provided 2016-01-11 criteria provided, single submitter clinical testing
Invitae RCV000233045 SCV000287668 pathogenic Progressive sclerosing poliodystrophy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 737 of the POLG protein (p.Gly737Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918054, ExAC 0.1%). This variant has been reported in combination with another POLG variant in individuals affected with POLG-related conditions (PMID: 18546365, 24725338, 19566497,18585914). Additionally this variant has been observed in combination with another rare POLG variant in two siblings affected with early-onset parkinsonism and peripheral neuropathy (PMID: 16634032). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in two siblings affected with ataxia neuropathy spectrum (PMID: 18195151). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 13513). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000370280 SCV000394280 pathogenic POLG-Related Spectrum Disorders 2016-06-14 criteria provided, single submitter clinical testing Across seven studies, the c.2209G>C (p.Gly737Arg) variant has been reported in at least 23 patients presenting with a range of phenotypes, including 20 in a compound heterozygous state (two of which were a sibling pair) and three in a heterozygous state (Davidzon et al. 2006; Horvath et al. 2006; Harrower et al. 2008; Wong et al. 2008; Tzoulis et al. 2009; Tang et al. 2011; Kullar et al. 2016). The p.Gly737Ag variant was found in two out of 1532 control alleles and is reported at a frequency of 0.00221 in the European American population of the Exome Sequencing Project. Kullar et al. (2016) demonstrated the variant resulted in cochlear dysfunction in four patients with POLG-related spectrum disorders and hearing loss. Based on the collective evidence, the p.Gly737Arg variant is classified as pathogenic for POLG-related spectrum disorders.
Athena Diagnostics Inc RCV000188568 SCV000614710 pathogenic not provided 2020-12-09 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 18546365, 21880868). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance (PMID: 30843307, 18195151). 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. Computational tools predict that this variant is damaging.
Mayo Clinic Laboratories, Mayo Clinic RCV000188568 SCV000802087 likely pathogenic not provided 2020-01-17 criteria provided, single submitter clinical testing PS4_moderate, PM3, PP1, PP3, PP5
Ambry Genetics RCV000720676 SCV000851555 pathogenic Seizures 2019-03-02 criteria provided, single submitter clinical testing The p.G737R pathogenic mutation (also known as c.2209G>C), located in coding exon 12 of the POLG gene, results from a G to C substitution at nucleotide position 2209. The glycine at codon 737 is replaced by arginine, an amino acid with dissimilar properties. This is a well described common POLG mutation, having been detected with a frequency of close to 4% of alleles in affected individuals. In several studies, it has been detected in the compound heterozygous state in individuals exhibiting a wide range of phenotypes: from adult onset muscle weakness, myopathy, and ataxia, to early onset liver failure, seizures, and childhood death (Davidzon G et al. Ann. Neurol., 2006 May;59:859-62; Farwell KD et al. Genet. Med., 2015 Jul;17:578-86; Tang S et al. J. Med. Genet., 2011 Oct;48:669-81; Weiss MD et al. Muscle Nerve, 2010 Jun;41:882-5; Milone M et al. Neuromuscul. Disord., 2008 Aug;18:626-32; Harrower T et al. Arch. Neurol., 2008 Jan;65:133-6; Horvath R et al. Brain, 2006 Jul;129:1674-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000233045 SCV000887112 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2209G>C (NP_002684.1:p.Gly737Arg) [GRCH38: NC_000015.10:g.89323460C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768053 SCV000898898 likely pathogenic Progressive sclerosing poliodystrophy; Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-06-29 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 13 p.Gly737Arg (c.2209G>C): This variant has been reported in the literature in several individuals with various presentations of POLG-related disease (neuropathy, seizures, chronic progressive external opthalmoplegia (CPEO), ptosis, myopathy or early parkinsonism) as compound heterozygotes, segregating with disease in at least 1 affected family member (Davidzon 2006 PMID:16634032, Horvath 2006 PMID:16621917, Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365, Tzoulis 2009 PMID:19566497, Tang 2011 PMID:21880868, Sitarz 2014 PMID:247253378, Rempe 2016 PMID:27185166). This variant has also been reported as heterozygous in at least 3 individuals with POLG-related presentations, as well as in 1 individual with Charcot-Marie-Tooth disease Type 2, segregating with disease in 1 sibling (Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365). This variant is present in 0.1% (162/126642) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121918054). This variant is present in ClinVar with several entries, though the interpretation among labs is inconsistent (Variation ID:13513). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but the high presence of this variant in the general population, variable clinical presentation in reported individuals and inconsistent community consensus interpretation of this variant suggests that further evidence for pathogenicity is required. Therefore, this variant classified as likely pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188568 SCV001149565 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004601 SCV001163771 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4B, MNGIE type criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000188568 SCV001446707 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000233045 SCV001448830 likely pathogenic Progressive sclerosing poliodystrophy 2019-07-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285939 SCV001472452 likely pathogenic none provided 2019-09-16 criteria provided, single submitter clinical testing The POLG c.2209G>C; p.Gly737Arg variant (rs121918054) is reported in the literature in multiple individuals with symptoms or diagnoses of a POLG-associated disorder, including mitochondrial DNA depletion syndrome, progressive external ophthalmoplegia, early-onset parkinsonism, and sensorimotor neuropathy (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Multiple affected individuals also carried a second pathogenic variant, with parental testing confirming compound heterozygosity of several probands (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Additionally, the p.Gly737Arg variant was reported to co-segregate with autosomal recessive disease in at least two families (Davidzon 2006, Harrower 2008). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (171/129104 alleles) in the Genome Aggregation Database. The glycine at codon 737 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Bereau M et al. The wide POLG-related spectrum: An integrated view. J Neurol Sci. 2016 Sep 15;368:70-6. Davidzon G et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006 May;59(5):859-62. Harrower T et al. POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease. Arch Neurol. 2008 Jan;65(1):133-6. Horvath R et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Milone M et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008 Aug;18(8):626-32. Stumpf JD et al. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol. 2013 Apr 1;5(4):a011395. Tzoulis C et al. Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations. Acta Neurol Scand Suppl. 2009;(189):38-41. Wong LJ et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008 Sep;29(9):E150-72.
OMIM RCV000014467 SCV000034718 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2006-05-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000233045 SCV000536802 likely pathogenic Progressive sclerosing poliodystrophy 2016-06-21 no assertion criteria provided research
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508744 SCV000575912 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing
Inherited Neuropathy Consortium RCV000188568 SCV001190062 uncertain significance not provided no assertion criteria provided provider interpretation

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.