ClinVar Genomic variation as it relates to human health
NM_001953.5(TYMP):c.622G>A (p.Val208Met)
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
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NM_001953.5(TYMP):c.622G>A (p.Val208Met)
Variation ID: 16663 Accession: VCV000016663.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50527612 (GRCh38) [ NCBI UCSC ] 22: 50966041 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 20, 2015 May 12, 2024 Feb 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001953.5:c.622G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001944.1:p.Val208Met missense NM_001113755.3:c.622G>A NP_001107227.1:p.Val208Met missense NM_001113756.3:c.622G>A NP_001107228.1:p.Val208Met missense NM_001257988.1:c.622G>A NP_001244917.1:p.Val208Met missense NM_001257989.1:c.622G>A NP_001244918.1:p.Val208Met missense NC_000022.11:g.50527612C>T NC_000022.10:g.50966041C>T NG_011860.1:g.7474G>A NG_016235.1:g.3828G>A LRG_727:g.7474G>A LRG_727t1:c.622G>A LRG_727p1:p.Val208Met LRG_727t2:c.622G>A LRG_727p2:p.Val208Met - Protein change
- V208M
- Other names
- Val>Met
- Canonical SPDI
- NC_000022.11:50527611:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00020
The Genome Aggregation Database (gnomAD) 0.00027
The Genome Aggregation Database (gnomAD), exomes 0.00033
Exome Aggregation Consortium (ExAC) 0.00035
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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TYMP | - | - |
GRCh38 GRCh37 |
451 | 1095 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000199543.31 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Feb 19, 2024 | RCV000018143.41 |
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. |
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Likely pathogenic
(Apr 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715396.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597777.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Jul 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: yes
Allele origin:
germline
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Department of Pathophysiology and Transplantation, University of Milan
Accession: SCV001438016.1
First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020 |
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Likely pathogenic
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893595.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Dec 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000252467.11
First in ClinVar: Oct 11, 2015 Last updated: Jan 15, 2023 |
Comment:
Reported with another pathogenic variant in a patient with adult-onset ptosis and ophthalmoparesis and decreased thymidine phosphorylase activity, but it is not known whether the … (more)
Reported with another pathogenic variant in a patient with adult-onset ptosis and ophthalmoparesis and decreased thymidine phosphorylase activity, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ronchi et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16178026, 19853446, 19748572, 21412940, 30487145, 32849836, 32384880, 34426522, 33300680) (less)
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Likely pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004207501.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Dec 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021571.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002231769.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 208 of the TYMP protein (p.Val208Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 208 of the TYMP protein (p.Val208Met). This variant is present in population databases (rs121913039, gnomAD 0.06%). This missense change has been observed in individual(s) with mitochondrial disease and/or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (PMID: 16178026, 32849836, 33300680). ClinVar contains an entry for this variant (Variation ID: 16663). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYMP protein function. Studies have shown that this missense change alters TYMP gene expression (PMID: 32849836). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813889.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: TYMP c.622G>A (p.Val208Met) results in a conservative amino acid change located in the Glycosyl transferase, family 3 domain (IPR000312) of the encoded protein … (more)
Variant summary: TYMP c.622G>A (p.Val208Met) results in a conservative amino acid change located in the Glycosyl transferase, family 3 domain (IPR000312) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251306 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (0.00033 vs 0.0011), allowing no conclusion about variant significance. c.622G>A has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type; Marti_2005, Ronchi_2020, Levy_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16178026, 32849836, 33300680). ClinVar contains an entry for this variant (Variation ID: 16663). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Aug 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153735.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2005)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038422.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2015 |
Comment on evidence:
In 2 unrelated women with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound … (more)
In 2 unrelated women with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound heterozygosity for 2 mutations in the ECGF1 gene. Both patients had a 2398G-A transition, resulting in a val208-to-met (V208M) substitution. In addition, 1 patient had a 3535G-C transversion, resulting in a gly311-to-arg substitution (G311R; 131222.0012), and the other had a 2381G-C transversion, resulting in an arg202-to-thr substitution (R202T; 131222.0013). The patients had onset of gastrointestinal symptoms at age 42 and 40 years, respectively. Biochemical analysis showed 15 to 16% residual enzyme activity in both patients, which likely accounted for the later onset. (less)
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Pathogenic
(Jan 14, 2016)
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no assertion criteria provided
Method: literature only
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Mitochondrial DNA depletion syndrome 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000264517.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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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 |
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Validation and clinical performance of a combined nuclear-mitochondrial next-generation sequencing and copy number variant analysis panel in a Canadian population. | Levy MA | American journal of medical genetics. Part A | 2021 | PMID: 33300680 |
TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis. | Ronchi D | Frontiers in genetics | 2020 | PMID: 32849836 |
High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
Mitochondrial Neurogastrointestinal Encephalopathy Disease. | Adam MP | - | 2016 | PMID: 20301358 |
A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy. | Torres-Torronteras J | Human mutation | 2011 | PMID: 21412940 |
Collated mutations in mitochondrial DNA (mtDNA) depletion syndrome (excluding the mitochondrial gamma polymerase, POLG1). | Poulton J | Biochimica et biophysica acta | 2009 | PMID: 19748572 |
Late-onset MNGIE due to partial loss of thymidine phosphorylase activity. | Martí R | Annals of neurology | 2005 | PMID: 16178026 |
Text-mined citations for rs121913039 ...
HelpRecord last updated May 12, 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.