ClinVar Genomic variation as it relates to human health
NM_080916.3(DGUOK):c.763_766dup (p.Phe256Ter)
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.763_766dup (p.Phe256Ter)
Variation ID: 8155 Accession: VCV000008155.11
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 2p13.1 2: 73958199-73958200 (GRCh38) [ NCBI UCSC ] 2: 74185326-74185327 (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 Aug 22, 2016 Apr 6, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_080916.3:c.763_766dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_550438.1:p.Phe256Ter nonsense NM_001318859.2:c.481_484dup NP_001305788.1:p.Phe162Ter nonsense NM_001318860.2:c.472_475dup NP_001305789.1:p.Phe159Ter nonsense NM_001318861.2:c.472_475dup NP_001305790.1:p.Phe159Ter nonsense NM_001318862.2:c.454_457dup NP_001305791.1:p.Phe153Ter nonsense NM_001318863.2:c.454_457dup NP_001305792.1:p.Phe153Ter nonsense NM_080916.2:c.763_766dupGATT NM_080918.3:c.499_502dup NP_550440.1:p.Phe168Ter nonsense NR_104029.1:n.336_339dup non-coding transcript variant NR_104030.1:n.310_313dup non-coding transcript variant NR_134893.2:n.417_420dup non-coding transcript variant NR_134894.2:n.565_568dup non-coding transcript variant NR_134895.2:n.229_232dup non-coding transcript variant NR_134896.2:n.399_402dup non-coding transcript variant NR_134897.2:n.609_612dup non-coding transcript variant NR_134898.2:n.533_536dup non-coding transcript variant NC_000002.12:g.73958201_73958204dup NC_000002.11:g.74185328_74185331dup NG_008044.1:g.36376_36379dup - Protein change
- F162*, F168*, F153*, F159*, F256*
- Other names
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- Canonical SPDI
- NC_000002.12:73958199:TGATT:TGATTGATT
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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.
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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
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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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DGUOK | - | - |
GRCh38 GRCh37 |
228 | 362 | |
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
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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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Mar 25, 2024 | RCV000008633.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV000485369.13 | |
DGUOK-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jul 25, 2023 | RCV004528095.1 |
Submissions - Germline
Classification
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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
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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
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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
(Jul 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807395.2
First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023 |
Comment:
ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM3 moderated
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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DGUOK-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029856.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: DGUOK c.763_766dupGATT (p.Phe256X), also referred to as c.796insTGAT in the literature, results in a premature termination codon and although nonsense mediated decay is … (more)
Variant summary: DGUOK c.763_766dupGATT (p.Phe256X), also referred to as c.796insTGAT in the literature, results in a premature termination codon and although nonsense mediated decay is not expected, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 251464 control chromosomes (gnomAD). c.763_766dupGATT has been reported in the literature as a biallelic genotype in individuals affected with DGUOK-Related Disorders including mitochondrial DNA depletion syndrome (e.g. Slama_2005, Mousson de Camaret_2007, Dimmock_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <5% of normal activity (e.g. Mousson de Camaret_2007). The following publications have been ascertained in the context of this evaluation (PMID: 18205204, 17073823, 16263314). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 02, 2021)
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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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Revvity Omics, Revvity
Accession: SCV003827548.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 09, 2017)
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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: SCV000568217.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The c.763_766dupGATT pathogenic variant in the DGUOK gene has been reported previously in association with mitochondrial depletion syndrome in several unrelated individuals who were homozygous … (more)
The c.763_766dupGATT pathogenic variant in the DGUOK gene has been reported previously in association with mitochondrial depletion syndrome in several unrelated individuals who were homozygous for c.763_766dupGATT or heterozygous for c.763_766dupGATT and another variant in the DGUOK gene (Mancuso et al., 2003; Dimmock et al., 2008; Villarroya et al., 2009Al-Hussaini et al., 2014). Fibroblasts from an individual homozygous for this variant showed 1-2.6% enzyme activity compared to controls (Mousson et al., 2007). The c.763_766dupGATT variant results in the normal codon, Phenylalanine 256, being replaced by a Stop codon, denoted p.F256X. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. (less)
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Pathogenic
(Dec 30, 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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Invitae
Accession: SCV003524725.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe256*) in the DGUOK gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Phe256*) in the DGUOK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the DGUOK protein. This variant is present in population databases (rs763706988, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 14568816, 16263314, 17073823, 18205204, 19265691, 24321534). This variant is also known as c.796insTGAT. ClinVar contains an entry for this variant (Variation ID: 8155). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: research
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805422.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Sep 01, 2002)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028842.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a patient with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), Salviati et al. (2002) identified a homozygous 4-bp duplication (GATT) at nucleotide 763 in the … (more)
In a patient with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), Salviati et al. (2002) identified a homozygous 4-bp duplication (GATT) at nucleotide 763 in the DGUOK gene, resulting in a frameshift and premature termination of the protein. The patient presented at 2 months of age with poor feeding, hypotonia, nystagmus, metabolic acidosis, hepatomegaly, and elevated liver enzymes. She died at 5 months of age. Both parents and an unaffected sister were heterozygous for the mutation. (less)
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Pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133206.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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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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Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure. | Al-Hussaini A | The Journal of pediatrics | 2014 | PMID: 24321534 |
Altered gene transcription profiles in fibroblasts harboring either TK2 or DGUOK mutations indicate compensatory mechanisms. | Villarroya J | Experimental cell research | 2009 | PMID: 19265691 |
Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. | Dimmock DP | Human mutation | 2008 | PMID: 18205204 |
Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. | Mousson de Camaret B | The Biochemical journal | 2007 | PMID: 17073823 |
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 |
Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes. | Mancuso M | Archives of neurology | 2003 | PMID: 14568816 |
Mitochondrial DNA depletion and dGK gene mutations. | Salviati L | Annals of neurology | 2002 | PMID: 12205643 |
Text-mined citations for rs763706988 ...
HelpRecord last updated May 19, 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.