ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1550G>T (p.Gly517Val) (rs61752783)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000223970 SCV000884403 benign not provided 2018-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716079 SCV000846912 likely benign Seizures 2017-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed by in vitro/ex vivo assays,In silico models in agreement (benign) ,Intact protein function observed in appropriate functional assay(s)
Athena Diagnostics Inc RCV000223970 SCV000843315 benign not provided 2017-09-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223970 SCV000608735 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768289 SCV000898901 uncertain significance 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 2018-05-24 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related disease in the heterozygous, compound and double heterozygous state, many of which are reported with significantly variable phenotypes (Horvath 2006 PMID:16621917, Wong 2008 PMID:18546365, Tang 2011 PMID:21880868, Staropoli 2012 PMID:22727047, Gailey 2013 PMID:23808377, Woodbridge 2013 PMID:22647225, DaPozzo 2017 PMID:28130605). However, this variant is present in 0.7% (925/126620) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752783). This variant is present in ClinVar with multiple different classifications, including several Likely Benign/Benign entries (Variation ID:65665). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In addition, functional studies suggest that this variant retains 80-90% of activity relative to wild-type (Kasiviswanathan 2011 PMID:21856450). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is too conflicting for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000223970 SCV000281444 likely benign not provided 2016-05-19 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Department of Neurology, University Hospital of Strasbourg RCV000186556 SCV000240098 pathogenic Camptocormia 2012-01-01 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000118011 SCV000111915 benign not specified 2014-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000118011 SCV000242169 benign not specified 2016-05-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
GeneReviews RCV000055881 SCV000086887 non-pathogenic Mitochondrial diseases 2012-10-11 no assertion criteria provided curation Converted during submission to Benign.
Genetic Services Laboratory, University of Chicago RCV000118011 SCV000152329 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing
Invitae RCV000229511 SCV000287664 benign Progressive sclerosing poliodystrophy 2017-12-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000118011 SCV000967286 likely benign not specified 2018-10-05 criteria provided, single submitter clinical testing The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% (92 5/126620) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/), including 3 homozygotes. In addition, function al studies demonstrate an effect indistinguishable from wild type.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000223970 SCV000802090 likely benign not provided 2016-03-08 no assertion criteria provided clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000229511 SCV000887270 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.

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