ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2209G>C (p.Gly737Arg) (rs121918054)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720676 SCV000851555 pathogenic Seizures 2017-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Athena Diagnostics Inc RCV000188568 SCV000614710 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
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; Cerebellar ataxia infantile with progressive external ophthalmoplegia; 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.
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
Division of Human Genetics,Children's Hospital of Philadelphia RCV000233045 SCV000536802 likely pathogenic Progressive sclerosing poliodystrophy 2016-06-21 no assertion criteria provided research
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.
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.
Invitae RCV000233045 SCV000287668 pathogenic Progressive sclerosing poliodystrophy 2018-12-05 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.
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000188568 SCV000802087 uncertain significance not provided 2016-02-26 no assertion criteria provided clinical testing
OMIM RCV000014467 SCV000034718 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2006-05-01 no assertion criteria provided literature only
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508744 SCV000575912 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing
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.

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