ClinVar Genomic variation as it relates to human health
NM_080916.3(DGUOK):c.749T>C (p.Leu250Ser)
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_080916.3(DGUOK):c.749T>C (p.Leu250Ser)
Variation ID: 488491 Accession: VCV000488491.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 73958187 (GRCh38) [ NCBI UCSC ] 2: 74185314 (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 Feb 8, 2018 Sep 16, 2024 Jul 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_080916.3:c.749T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_550438.1:p.Leu250Ser missense NM_001318859.2:c.467T>C NP_001305788.1:p.Leu156Ser missense NM_001318860.2:c.458T>C NP_001305789.1:p.Leu153Ser missense NM_001318861.2:c.458T>C NP_001305790.1:p.Leu153Ser missense NM_001318862.2:c.440T>C NP_001305791.1:p.Leu147Ser missense NM_001318863.2:c.440T>C NP_001305792.1:p.Leu147Ser missense NM_080918.3:c.485T>C NP_550440.1:p.Leu162Ser missense NR_104029.1:n.352A>G non-coding transcript variant NR_104030.1:n.326A>G non-coding transcript variant NR_134893.2:n.403T>C non-coding transcript variant NR_134894.2:n.551T>C non-coding transcript variant NR_134895.2:n.215T>C non-coding transcript variant NR_134896.2:n.385T>C non-coding transcript variant NR_134897.2:n.595T>C non-coding transcript variant NR_134898.2:n.519T>C non-coding transcript variant NC_000002.12:g.73958187T>C NC_000002.11:g.74185314T>C NG_008044.1:g.36362T>C - Protein change
- L250S, L156S, L147S, L153S, L162S
- Other names
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- Canonical SPDI
- NC_000002.12:73958186:T:C
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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.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
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
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. |
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DGUOK | - | - |
GRCh38 GRCh37 |
233 | 369 | |
DGUOK-AS1 | - | - | - | GRCh38 | - | 50 |
Conditions - Germline
Condition
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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
Help
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jul 3, 2024 | RCV000578402.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2023 | RCV001564282.6 | |
See cases
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no classifications from unflagged records (1) |
no classifications from unflagged records
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May 17, 2024 | RCV002252170.3 |
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
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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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Pathogenic
(Nov 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680187.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Pathogenic
(May 29, 2019)
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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: SCV001787425.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Published functional studies demonstrate a damaging effect with less than 1% residual deoxyguanosine kinase activity compared to wild-type (Wang et al., 2005); In silico analysis, … (more)
Published functional studies demonstrate a damaging effect with less than 1% residual deoxyguanosine kinase activity compared to wild-type (Wang et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 28411097, 19265691, 26342080, 15639197, 18600543, 19125351, 18205204, 24478274, 19380071, 16263314, 17452231, 16908739, 29228108, 17280874, 22602837, 19094978, 30693370) (less)
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Pathogenic
(Jul 19, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003524665.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15639197, 16263314, 16908739, 17452231). ClinVar contains an entry for this variant … (more)
This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15639197, 16263314, 16908739, 17452231). ClinVar contains an entry for this variant (Variation ID: 488491). This variant is present in population databases (rs749464475, gnomAD 0.009%). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the DGUOK protein (p.Leu250Ser). 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 DGUOK protein function. Experimental studies have shown that this missense change affects DGUOK function (PMID: 15639197). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005203727.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: DGUOK c.749T>C (p.Leu250Ser) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Five … (more)
Variant summary: DGUOK c.749T>C (p.Leu250Ser) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251466 control chromosomes. c.749T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mitochondrial DNA depletion syndrome 3 (Wang_2005, Freisinger_2006, Capalbo_2019, Bychkov_2021, Guzman_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in residual activity of mutant protein compared to the wild type in an in vitro assay (Wang_2005). The following publications have been ascertained in the context of this evaluation (PMID: 33486010, 31589614, 16908739, 38027095, 15639197). ClinVar contains an entry for this variant (Variation ID: 488491). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Uncertain significance
(Oct 15, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523294.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PM2, PM3, PP3
Clinical Features:
Neurodevelopmental abnormality (present) , Microcephaly (present) , Abnormal cerebral subcortex morphology (present)
Geographic origin: Brazil
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Case report: Two unexpected cases of DGUOK-related mitochondrial DNA depletion syndrome presenting with hyperinsulinemic hypoglycemia. | Guzman H | Frontiers in endocrinology | 2023 | PMID: 38027095 |
Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes. | Bychkov IO | Mitochondrion | 2021 | PMID: 33486010 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Altered gene transcription profiles in fibroblasts harboring either TK2 or DGUOK mutations indicate compensatory mechanisms. | Villarroya J | Experimental cell research | 2009 | PMID: 19265691 |
Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. | Sarzi E | The Journal of pediatrics | 2007 | PMID: 17452231 |
Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. | Freisinger P | Archives of neurology | 2006 | PMID: 16908739 |
Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement. | Slama A | Molecular genetics and metabolism | 2005 | PMID: 16263314 |
Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. | Wang L | Molecular genetics and metabolism | 2005 | PMID: 15639197 |
Text-mined citations for rs749464475 ...
HelpRecord last updated Oct 08, 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.