ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1760C>T (p.Pro587Leu)

gnomAD frequency: 0.00160  dbSNP: rs113994096
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Total submissions: 44
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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
Eurofins NTD LLC (GA) 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 2021-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (rs113994096, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) 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: 12210792, 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). 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: 13505). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Institute of Human Genetics, Klinikum rechts der Isar RCV000186576 SCV000680342 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2017-11-08 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000020473 SCV000746435 pathogenic Mitochondrial DNA depletion syndrome 1 2017-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716826 SCV000847670 pathogenic Seizure 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 Center for Human Genetics Tuebingen RCV000427845 SCV001149568 pathogenic not provided 2022-04-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004602 SCV001163772 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 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]
Kariminejad - Najmabadi Pathology & Genetics Center RCV001813986 SCV001755620 pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
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 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)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001770037 SCV002011121 likely pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 2021-11-03 criteria provided, single submitter clinical testing
DASA RCV001813743 SCV002061213 pathogenic POLG-related disorders 2022-01-05 criteria provided, single submitter clinical testing The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; 25660390; 12975295; 1539879; 19578034; 24265579; 23448099;25742477; 26224072) - PS4.The p.(Pro587Leu) was detected in trans with a pathogenic variant (PMID: 19578034) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 25660390) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic.
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV001847603 SCV002105557 likely pathogenic Hereditary spastic paraplegia 2021-11-22 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000427845 SCV002503521 likely pathogenic not provided 2022-03-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV002227034 SCV002506434 uncertain significance Stroke 2021-12-08 criteria provided, single submitter clinical testing ACMG categories: PM1,PM2,PP3,BP1
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV001004602 SCV002512294 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b 2022-02-15 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong, PP3 supporting
Genetics and Molecular Pathology, SA Pathology RCV000014456 SCV002556643 likely pathogenic Mitochondrial DNA depletion syndrome 4b 2020-12-22 criteria provided, single submitter clinical testing This sequence change in exon 10 of 23 replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (gnomAD 433/281158 heterozygotes, 1 homozygote) (PM2). The variant has been reported in dbSNP (rs113994096). The variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it has been observed on the same chromosome (in cis) with the second (p.Thr251Ile) variant also detected in this patient (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868) (PS4_moderate). In many of these previously reported cases, the two variants in cis were observed on the opposite chromosome (in trans) from a third, pathogenic variant in an affected individual. The p.Pro587Leu and p.Thr251Ile variant combination in cis accounts for approximately 6% of disease-causing alleles in POLG-related disorders, mainly in Caucasians (PMID: 21880868). The p.Pro587Leu and Thr251Ile variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879) (PP1_moderate). Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3).The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 28544). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV001813743 SCV002568173 pathogenic POLG-related disorders 2022-06-02 criteria provided, single submitter clinical testing PS3, PM3_Strong, PP1, PP3
3billion RCV000186576 SCV002572626 likely pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013505). The variant was observed in cis with NM_002693.3:c.752C>T (p.Thr251Ile) in many individuals affected with POLG-related diseases (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center RCV000186576 SCV002581640 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2022-07-29 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000186576 SCV002587017 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2021-07-27 criteria provided, single submitter research
OMIM RCV000014456 SCV000034706 pathogenic Mitochondrial DNA depletion syndrome 4b 2004-09-01 no assertion criteria provided literature only
GeneReviews RCV000508752 SCV000040907 not provided Mitochondrial disease no assertion provided literature only
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 disease 2017-04-07 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000427845 SCV001952060 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000427845 SCV001971389 pathogenic not provided no assertion criteria provided clinical testing

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