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

gnomAD frequency: 0.00096  dbSNP: rs121918054

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188568	SCV000225831	pathogenic	not provided	2018-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000188568	SCV000242188	pathogenic	not provided	2020-02-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16634032, 24725338, 18546365, 25356970, 30609409, 31521625, 16621917, 21880868, 19566497, 27185166, 27016405, 27349602, 28812649, 29655203, 30843307, 31731261, 31980526, 34062649, 33300680, 33726816)
Laboratory for Molecular Medicine, Mass General Brigham 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233045	SCV000287668	pathogenic	Progressive sclerosing poliodystrophy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 737 of the POLG protein (p.Gly737Arg). This variant is present in population databases (rs121918054, gnomAD 0.1%), 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 conditions (PMID: 16634032, 18546365, 18585914, 19566497, 24725338). 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: 13513). 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%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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	RCV000188568	SCV000614710	pathogenic	not provided	2023-07-11	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 has been identified in multiple unrelated individuals with autosomal recessive POLG-related disorders and appears to segregate with disease in at least one family. Affected heterozygous individuals have also been reported. 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	2023-05-25	criteria provided, single submitter	clinical testing	PP1, PP3, PM3, PS4_moderate
Ambry Genetics	RCV002316196	SCV000851555	pathogenic	Inborn genetic diseases	2023-11-17	criteria provided, single submitter	clinical testing	The c.2209G>C (p.G737R) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2209, causing the glycine (G) at amino acid position 737 to be replaced by an arginine (R). for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant POLG-related progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.07% (211/282774) total alleles studied. The highest observed frequency was 0.13% (171/129104) of European (non-Finnish) alleles. 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, neuropathy, and ataxia, to early onset liver failure, seizures, and childhood death (Davidzon, 2006; Horvath, 2006; Harrower, 2008; Milone, 2008; Tzoulis, 2009; Tang, 2011; Rempe, 2016; Farwell, 2015; Phillips, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
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; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2021-03-30	criteria provided, single submitter	clinical testing	POLG NM_002693 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 Center for Human Genetics Tuebingen	RCV000188568	SCV001149565	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2:Supporting, PP3
Baylor Genetics	RCV001004601	SCV001163771	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		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	RCV000188568	SCV001472452	likely pathogenic	not 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.
Revvity Omics, Revvity	RCV000188568	SCV002019467	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000233045	SCV002059312	likely pathogenic	Progressive sclerosing poliodystrophy	2020-12-16	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001813987	SCV002061731	likely pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2021-12-22	criteria provided, single submitter	clinical testing	PM3_Strong, PP1, PP3
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847605	SCV002105566	pathogenic	Hereditary spastic paraplegia	2019-12-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000188568	SCV002503262	likely pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000370280	SCV002548249	pathogenic	POLG-Related Spectrum Disorders	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2209G>C (p.Gly737Arg) results in a non-conservative amino acid change located in the linker region (Wong_2008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251378 control chromosomes. c.2209G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders (example, Davidzon_2006, Milone_2008, Wong_2008, Tzoulis_2009, Stewart_2011, Sitarz_2014, Phillips_2019, Bychkov_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000014467	SCV002580308	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2021-09-16	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000233045	SCV002761933	likely pathogenic	Progressive sclerosing poliodystrophy	2021-07-08	criteria provided, single submitter	clinical testing	The POLG c.2209G>C variant is classified as Likely Pathogenic (PS4_Moderate, PM3_Strong, PP3, PP5)
Baylor Genetics	RCV000233045	SCV004205838	pathogenic	Progressive sclerosing poliodystrophy	2024-03-27	criteria provided, single submitter	clinical testing
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 disease	2017-04-07	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000188568	SCV001190062	uncertain significance	not provided		no assertion criteria provided	provider interpretation
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003318542	SCV004022484	likely pathogenic	Tip-toe gait	2023-01-10	no assertion criteria provided	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003985721	SCV004115188	likely pathogenic	POLG-related disorder	2024-09-01	no assertion criteria provided	clinical testing	The POLG c.2209G>C variant is predicted to result in the amino acid substitution p.Gly737Arg. This variant has been reported along with a second POLG variant in several individuals with mitochondrial DNA maintenance disorders which include progressive external opthalmoplegia, Charcot-Marie-Tooth Disease, and early-onset Parkinsonism; this variant was reported to co-segregate with autosomal recessive disease in at least two families (see, for example, Davidzon et al. 2006. PubMed ID: 16634032; Harrower et al. 2008. PubMed ID: 18195151; supplementary data, Tang et al, 2011. PMID: 21880868). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a cause of autosomal dominant disease. This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13513). Given all the evidence, we interpret c.2209G>C (p.Gly737Arg) as likely pathogenic for autosomal recessive POLG-related disorders.