ClinVar Miner

Submissions for variant NM_001126131.2(POLG):c.1760C>T (p.Pro587Leu) (rs113994096)

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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193529 SCV000248555 pathogenic not specified 2019-07-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000427845 SCV000331603 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415307 SCV000492823 pathogenic Global developmental delay 2014-07-15 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000427845 SCV000511317 pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing
Invitae RCV000408293 SCV000543885 uncertain significance Progressive sclerosing poliodystrophy 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases, including a homozygous individual (rs113994096, 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.Thr251Ile) variant (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). 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 one or both of these variants 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:13505). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 the population databases. Furthermore, because it almost always occurs in cis with p.Thr251Ile, 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.
Athena Diagnostics Inc RCV000427845 SCV000614707 pathogenic not provided 2019-04-16 criteria provided, single submitter clinical testing This variant is seen in cis with POLG c.752C>T (p.Thr251Ile). 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. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000020473 SCV000746435 pathogenic Mitochondrial DNA depletion syndrome 1 (MNGIE type) 2017-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716826 SCV000847670 pathogenic Seizures 2018-11-30 criteria provided, single submitter clinical testing The p.P587L pathogenic mutation (also known as c.1760C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at nucleotide position 1760. The proline at codon 587 is replaced by leucine, an amino acid with similar properties. This mutation has been reported to occur almost exclusively in cis with p.T251I (c.752C>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, autosomal recessive external ophthalmoplegia<span style="color:rgb(169, 169, 169); font-family:arial,sans-serif; font-size:12px"> (arPEO), neuropathy, myopathy, MNGIE, intellectual disability and various other POLG-deficiency symptoms (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.T251I in conjunction with the p.R853W alteration (phase was not confirmed) in an individual with PEO, ptosis, and multiple mtDNA deletions (Gonz&aacute;lez-Vioque E et al. Arch. Neurol., 2006 Jan;63:107-11). In addition, biochemical characterization of P587L 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 P587L alone (DeBalsi KL et al. J. Biol. Chem., 2017 03;292:4198-4209). Based on the supporting evidence, p.P587L is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000427845 SCV000884404 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000408293 SCV000886904 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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.
Mendelics RCV000408293 SCV001139681 uncertain significance Progressive sclerosing poliodystrophy 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000427845 SCV001149568 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004602 SCV001163772 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 RCV000427845 SCV001446808 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000408293 SCV001448887 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 RCV001642226 SCV001519175 pathogenic Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 2021-01-04 criteria provided, single submitter research
Baylor Genetics RCV000408293 SCV001529893 pathogenic Progressive sclerosing poliodystrophy 2018-06-28 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. These two variants have been previously reported as pathogenic and are frequently in cis configuration [PMID 12210792, 19189930, 23665194, 28154168, 22616202, 25585994, 23783014, 26468652, 19566497, 20513108, 24122062]
Genomics England Pilot Project,Genomics England RCV000408293 SCV001760353 likely pathogenic Progressive sclerosing poliodystrophy criteria provided, single submitter clinical testing
Practice for Gait Abnormalities, David Pomarino,Competency Network Toe Walking c/o Practice Pomarino RCV001610290 SCV001832553 pathogenic Toe walking 2021-02-10 criteria provided, single submitter clinical testing c.1760C>T p.(Pro587Leu) [dbSNP: rs113994096, Frequenz: 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 RCV000014456 SCV001950111 uncertain significance Mitochondrial DNA depletion syndrome 4B, MNGIE type 2021-07-27 criteria provided, single submitter clinical testing Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)
OMIM RCV000014456 SCV000034706 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2004-09-01 no assertion criteria provided literature only
GeneReviews RCV000020473 SCV000040907 pathologic Mitochondrial DNA depletion syndrome 1 (MNGIE type) 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000186576 SCV000240152 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2004-09-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000408293 SCV000536728 pathogenic Progressive sclerosing poliodystrophy 2016-12-12 no assertion criteria provided research
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508752 SCV000575915 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000186576 SCV000680342 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 RCV000427845 SCV000802089 likely pathogenic not provided 2016-03-08 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000427845 SCV001740685 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000427845 SCV001807948 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000427845 SCV001926715 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000427845 SCV001952060 likely pathogenic not provided no assertion criteria provided clinical testing

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