ClinVar Miner

Submissions for variant NM_001126131.2(POLG):c.752C>T (p.Thr251Ile) (rs11394094)

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000184009 SCV000236523 pathogenic Progressive sclerosing poliodystrophy 2014-05-12 criteria provided, single submitter clinical testing
GeneDx RCV000188641 SCV000242264 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing The T251I missense variant in the POLG gene has been reported previously in association with several POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). The T251I missense variant is typically found on the same allele (in cis) with the P587L variant and together they account for approximately 6% of disease-causing alleles in the POLG gene (Tang et al., 2011); however, the P587L variant was not observed in this patient. The T251I variant is observed in 195/66,122 (0.3%) alleles from individuals of European background, including 1 unrelated homozygous individual in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T251I 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. However, this substitution alters at a poorly conserved residue predicted to be in the exonuclease domain. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret T251I as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000194055 SCV000248561 pathogenic not specified 2019-07-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188641 SCV000332083 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000262479 SCV000394298 pathogenic POLG-Related Spectrum Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.752C>T (p.Thr251Ile) variant is well described in the literature and has been reported across 11 studies in which it has been found in 36 individuals affected with POLG-related spectrum disorders covering a wide range of phenotypes (Van Goethem et al., 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Gáti et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013). In all but one of the reported cases, the p.Thr251Ile variant has been found in cis with p.Pro587Leu as the complex allele [p.Thr251Ile; p.Pro587Leu]. Twenty-four of the reported cases are compound heterozygotes with a third variant in trans to the complex allele, five cases are homozygous for the complex allele and six are heterozygotes. The one instance where the p.Thr251Ile variant was found independently was in a compound heterozygote state with another missense variant in one individual (Gati et al. 2011). The complex allele has been found in 5/2040 control alleles and the p.Thr251Ile variant alone is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Thr251Ile variant is classified as pathogenic for POLG-related spectrum disorders when found as part of the complex allele and of unknown significance but suspicious for pathogenicity for POLG-related spectrum disorders when found independently.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415105 SCV000492822 pathogenic Global developmental delay 2014-07-15 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188641 SCV000511806 uncertain significance not provided 2017-04-17 criteria provided, single submitter clinical testing
Invitae RCV000184009 SCV000543870 uncertain significance Progressive sclerosing poliodystrophy 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases, including a homozygous individual (rs113994094, ExAC 0.3%). This variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Pro587Leu) variant (PMID: 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In many of these cases, these two variants in cis were observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual. These findings are consistent with autosomal recessive inheritance, and suggest that these variants in cis contribute to disease. Furthermore, these two variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879). ClinVar contains an entry for this variant (Variation ID: 13503). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, it has also been observed in unaffected individuals and in population databases. Furthermore, because it almost always occurs in cis with p.Pro587Leu, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000020484 SCV000746436 likely pathogenic Mitochondrial DNA depletion syndrome 1 (MNGIE type) 2017-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716828 SCV000847672 pathogenic Seizures 2018-10-09 criteria provided, single submitter clinical testing The p.T251I pathogenic mutation (also known as c.752C>T), located in coding exon 2 of the POLG gene, results from a C to T substitution at nucleotide position 752. The threonine at codon 251 is replaced by isoleucine, an amino acid with similar properties. This mutation has been reported to occur almost exclusively in cis with p.P587L (c.1760C>T) and this syntenic mutation combination accounts for approximately 6% of all disease causing alleles in POLG (Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). This syntenic mutation combination has been detected alone, in trans with various other POLG mutations and alterations, and as homozygous, in individuals with Alpers syndrome, possible Kearns-Sayre syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability and various other POLG-deficiency symptoms (Dames S et al. J Mol Diagn, 2013 Jul;15:526-34; Van Goethem G et al. Eur. J. Hum. Genet., 2003 Jul;11:547-9; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Uusimaa J et al. Epilepsia, 2013 Jun;54:1002-11; Weiss MD et al. Muscle Nerve, 2010 Jun;41:882-5; Horvath R et al. Brain, 2006 Jul;129:1674-84; Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). Of note, this mutation has been detected without p.P587L (c.1760C>T) in an individual with Parkinson disease without another POLG alteration and in another individual who also carried POLG p.G848S (phase was not confirmed) with sensory ataxic neuropathy, dysarthria/dysphagia and external ophthalmoplegia (SANDO) (Gáti I et al. Acta Myol, 2011 Dec;30:188-90; Gui YX et al. Parkinsonism Relat. Disord., 2015 Mar;21:282-6). In addition, biochemical characterization of T251I mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than T251I alone (DeBalsi KL et al. J. Biol. Chem., 2017 03;292:4198-4209). Based on the supporting evidence, p.T251I is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000188641 SCV000884405 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000184009 SCV000886920 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.752C>T (NP_002684.1:p.Thr251Ile) [GRCH38: NC_000015.10:g.89330184G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Mendelics RCV000184009 SCV001139686 uncertain significance Progressive sclerosing poliodystrophy 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000188641 SCV001145168 pathogenic not provided 2019-04-16 criteria provided, single submitter clinical testing Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188641 SCV001149577 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004407 SCV001163401 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4B, MNGIE type criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000184009 SCV001440553 uncertain significance Progressive sclerosing poliodystrophy 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000188641 SCV001446809 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000184009 SCV001448886 likely pathogenic Progressive sclerosing poliodystrophy 2019-01-10 criteria provided, single submitter clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit,IRCCS Fondazione Stella Maris RCV001642225 SCV001519176 pathogenic Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 2021-01-04 criteria provided, single submitter research
Practice for Gait Abnormalities, David Pomarino,Competency Network Toe Walking c/o Practice Pomarino RCV001678594 SCV001810055 pathogenic Toe walking 2021-02-10 criteria provided, single submitter clinical testing The variant c.752C> T p. (Thr251Ile) [dbSNP: rs113994094, frequency: A = 0.15%, GnomAD] is rated by the majority (15 entries) as "probably pathogenic" and "pathogenic" in the ClinVar mutation database.
Institute of Human Genetics, University of Leipzig Medical Center RCV000014448 SCV001950112 uncertain significance Mitochondrial DNA depletion syndrome 4B, MNGIE type 2021-07-27 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous with NM_001126131.2:c.1760C>T.
OMIM RCV000014447 SCV000034697 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2004-09-01 no assertion criteria provided literature only
OMIM RCV000014448 SCV000034698 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2004-09-01 no assertion criteria provided literature only
GeneReviews RCV000020484 SCV000040921 pathologic Mitochondrial DNA depletion syndrome 1 (MNGIE type) 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000184009 SCV000536729 pathogenic Progressive sclerosing poliodystrophy 2016-12-12 no assertion criteria provided research
Institute of Human Genetics, Klinikum rechts der Isar RCV000014447 SCV000680344 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2017-11-08 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000188641 SCV000802095 likely pathogenic not provided 2016-03-08 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000188641 SCV001741648 pathogenic not provided no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV000184009 SCV001760354 likely pathogenic Progressive sclerosing poliodystrophy no assertion criteria provided clinical testing

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