ClinVar Genomic variation as it relates to human health
NM_001953.5(TYMP):c.866A>C (p.Glu289Ala)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001953.5(TYMP):c.866A>C (p.Glu289Ala)
Variation ID: 16653 Accession: VCV000016653.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50526638 (GRCh38) [ NCBI UCSC ] 22: 50965067 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 17, 2024 Mar 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001953.5:c.866A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001944.1:p.Glu289Ala missense NM_001113755.3:c.866A>C NP_001107227.1:p.Glu289Ala missense NM_001113756.3:c.866A>C NP_001107228.1:p.Glu289Ala missense NM_001257988.1:c.866A>C NP_001244917.1:p.Glu289Ala missense NM_001257989.1:c.866A>C NP_001244918.1:p.Glu289Ala missense NC_000022.11:g.50526638T>G NC_000022.10:g.50965067T>G NG_011860.1:g.8448A>C NG_016235.1:g.4802A>C NG_021419.1:g.23423T>G LRG_727:g.8448A>C LRG_727t1:c.866A>C LRG_727p1:p.Glu289Ala LRG_727t2:c.866A>C LRG_727p2:p.Glu289Ala P19971:p.Glu289Ala - Protein change
- E289A
- Other names
- Glu>Ala
- Canonical SPDI
- NC_000022.11:50526637:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
TYMP | - | - |
GRCh38 GRCh37 |
456 | 1101 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 22, 2024 | RCV000018133.38 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2023 | RCV000498727.10 | |
Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001276276.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893594.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Oct 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915979.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
|
|
Pathogenic
(Jul 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 1
Affected status: yes
Allele origin:
germline
|
Department of Pathophysiology and Transplantation, University of Milan
Accession: SCV001438020.1
First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020 |
|
|
Pathogenic
(Aug 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589522.5
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
|
|
Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207510.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823768.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Nov 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001233268.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
Pathogenic
(Jan 29, 1999)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038412.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 3371A-C transversion in … (more)
In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 3371A-C transversion in exon 7 of the ECGF1 gene, resulting in a glu289-to-ala (E289A) substitution. This mutation was seen in homozygosity in an Ashkenazi Jewish patient and in compound heterozygosity in 4 other patients of German American (131222.0002), German (131222.0006), English (131222.0008), and European American ancestry. The mutation was associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion. (less)
|
|
Pathogenic
(Jan 14, 2016)
|
no assertion criteria provided
Method: literature only
|
Mitochondrial DNA depletion syndrome 1
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000264527.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Mitochondrial neurogastrointestinal encephalomyopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462370.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Mitochondrial Neurogastrointestinal Encephalopathy Disease. | Adam MP | - | 2016 | PMID: 20301358 |
MNGIE Syndrome: Liver Cirrhosis Should Be Ruled Out Prior to Bone Marrow Transplantation. | Finkenstedt A | JIMD reports | 2013 | PMID: 23430799 |
Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis. | Scarpelli M | Case reports in neurology | 2012 | PMID: 23341816 |
Biochemical abnormalities in a patient with thymidine phosphorylase deficiency with fatal outcome. | Bakker JA | Journal of inherited metabolic disease | 2010 | PMID: 20151198 |
Frequency of mitochondrial defects in patients with chronic intestinal pseudo-obstruction. | Amiot A | Gastroenterology | 2009 | PMID: 19344718 |
Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome. | Slama A | Molecular genetics and metabolism | 2005 | PMID: 15781193 |
Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. | Nishino I | Annals of neurology | 2000 | PMID: 10852545 |
Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. | Nishino I | Science (New York, N.Y.) | 1999 | PMID: 9924029 |
Text-mined citations for rs121913036 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.