ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1760C>T (p.Pro587Leu) (rs113994096)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000427845 SCV000884404 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716826 SCV000847670 pathogenic Seizures 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Athena Diagnostics Inc RCV000427845 SCV000614707 uncertain significance not provided 2016-06-17 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
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415307 SCV000492823 pathogenic Global developmental delay 2014-07-15 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000408293 SCV000536728 pathogenic Progressive sclerosing poliodystrophy 2016-12-12 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000427845 SCV000331603 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
GeneReviews RCV000020473 SCV000040907 pathologic Mitochondrial DNA depletion syndrome 1 (MNGIE type) 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000193529 SCV000248555 uncertain significance not specified 2014-06-24 criteria provided, single submitter clinical testing
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
Institute of Human Genetics,Klinikum rechts der Isar RCV000186576 SCV000680342 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2017-11-08 criteria provided, single submitter clinical testing
Invitae RCV000408293 SCV000543885 uncertain significance Progressive sclerosing poliodystrophy 2018-12-27 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000427845 SCV000802089 likely pathogenic not provided 2016-03-08 no assertion criteria provided clinical testing
OMIM RCV000014456 SCV000034706 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2004-09-01 no assertion criteria provided literature only
OMIM RCV000186576 SCV000240152 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2004-09-01 no assertion criteria provided literature only
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508752 SCV000575915 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided 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.

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