ClinVar Miner

Submissions for variant NM_001953.5(TYMP):c.866A>C (p.Glu289Ala)

gnomAD frequency: 0.00005  dbSNP: rs121913036
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498727 SCV000589522 pathogenic not provided 2025-01-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19344718, 20151198, 10852545, 18787099, 21503690, 9924029, 24199812, 23430799, 23341816, 19748572, 19221117, 31267951, 33300680, 32849836)
Fulgent Genetics, Fulgent Genetics RCV000018133 SCV000893594 pathogenic Mitochondrial DNA depletion syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000018133 SCV000915979 pathogenic Mitochondrial DNA depletion syndrome 1 2018-10-09 criteria provided, single submitter clinical testing The TYMP c.866A>C (p.Glu289Ala) missense variant has been reported in at least five studies and is found in a total of 12 individuals with mitochondrial neurogastrointestinal encophalopathy disease (MNGIE), including in at least four in a homozygous state and in eight in a compound heterozygous state (Nishino et al. 1999; Amiot et al. 2009; Bakker et al. 2010; Scarpelli et al. 2012; Finkenstedt et al. 2012). As of 2010, fewer than 70 individuals with features consistent with MNGIE had been reported, according to Gene Reviews (Shoffner, 2010). The p.Glu289Ala variant was absent from 63 control subjects and is reported at a frequency of 0.000604 in the Ashkenazi Jewish population of the Genome Aggregation Database. Assays of TYMP activity level in peripheral leukocytes from six affected individuals, including one homozygote and two compound heterozygotes with the p.Glu289Ala variant, and 19 controls revealed that probands had either no detectable TYMP activity or activity that was less than 5% of controls (Nishino et al. 1999). Based on the evidence, the p.Glu289Ala variant is classified as pathogenic for mitochondrial neurogastrointestinal encophalopathy disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV000498727 SCV001233268 pathogenic not provided 2024-04-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 289 of the TYMP protein (p.Glu289Ala). This variant is present in population databases (rs121913036, gnomAD 0.06%). This missense change has been observed in individuals with TYMP-related conditions (PMID: 9924029, 10852545, 15781193, 20151198, 23341816). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYMP protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Department of Pathophysiology and Transplantation, University of Milan RCV000018133 SCV001438020 pathogenic Mitochondrial DNA depletion syndrome 1 2020-07-04 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000018133 SCV003823768 pathogenic Mitochondrial DNA depletion syndrome 1 2023-08-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000018133 SCV004207510 pathogenic Mitochondrial DNA depletion syndrome 1 2024-03-22 criteria provided, single submitter clinical testing
OMIM RCV000018133 SCV000038412 pathogenic Mitochondrial DNA depletion syndrome 1 1999-01-29 no assertion criteria provided literature only
GeneReviews RCV000018133 SCV000264527 pathogenic Mitochondrial DNA depletion syndrome 1 2016-01-14 no assertion criteria provided literature only
Natera, Inc. RCV001276276 SCV001462370 pathogenic Mitochondrial neurogastrointestinal encephalomyopathy 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.