ClinVar Genomic variation as it relates to human health
NM_080916.3(DGUOK):c.137A>G (p.Asn46Ser)
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.137A>G (p.Asn46Ser)
Variation ID: 253062 Accession: VCV000253062.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 73927047 (GRCh38) [ NCBI UCSC ] 2: 74154174 (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 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_080916.3:c.137A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_550438.1:p.Asn46Ser missense NM_001318859.2:c.137A>G NP_001305788.1:p.Asn46Ser missense NM_001318860.2:c.-42A>G 5 prime UTR NM_001318861.2:c.-128A>G 5 prime UTR NM_001318862.2:c.-128A>G 5 prime UTR NM_001318863.2:c.-42A>G 5 prime UTR NM_080918.3:c.137A>G NP_550440.1:p.Asn46Ser missense NR_134893.2:n.168A>G non-coding transcript variant NR_134894.2:n.168A>G non-coding transcript variant NR_134895.2:n.168A>G non-coding transcript variant NR_134896.2:n.168A>G non-coding transcript variant NR_134897.2:n.168A>G non-coding transcript variant NR_134898.2:n.168A>G non-coding transcript variant NC_000002.12:g.73927047A>G NC_000002.11:g.74154174A>G NG_008044.1:g.5222A>G Q16854:p.Asn46Ser - Protein change
- N46S
- Other names
- -
- Canonical SPDI
- NC_000002.12:73927046:A:G
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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 | ||
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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. |
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DGUOK | - | - |
GRCh38 GRCh37 |
228 | 362 | |
LOC129934096 | - | - | - | GRCh38 | - | 74 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2007 | RCV000239535.11 | |
Likely pathogenic (1) |
no assertion criteria provided
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Mar 31, 2016 | RCV000239586.11 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV001550857.12 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2007 | RCV001799645.11 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2007 | RCV001824706.9 |
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 26, 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: SCV001771254.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 23968935, 26874653, 17452231, 23043144, 18205204, 17073823, 29137425, 18825706) (less)
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Pathogenic
(Nov 27, 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: SCV003524694.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 46 of the DGUOK protein (p.Asn46Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 46 of the DGUOK protein (p.Asn46Ser). This variant is present in population databases (rs763615602, gnomAD 0.006%). This missense change has been observed in individuals with a spectrum of autosomal recessive mitochondrial disorders (PMID: 17073823, 17452231, 18205204, 23043144, 26874653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253062). 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 DGUOK protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000297857.3
First in ClinVar: Aug 22, 2016 Last updated: Aug 07, 2021 |
Comment on evidence:
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson … (more)
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson De Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene: a c.137A-G transition (c.137A-G, NM_080916) in exon 1, resulting in an asn46-to-ser (N46S) substitution at a conserved residue in the P-loop domain, and a c.797T-G transversion in exon 6, resulting in a leu266-to-arg (L266R; 601465.0009) substitution in the C-terminal alpha-9 helix domain. The patient had a very unusual disease course: he presented in infancy with severe liver disease, but then had spontaneous improvement beginning at about 32 months of age. He showed normal development by 4 years of age and ultimately had almost complete reversal of the phenotype; he never had neurologic involvement. In vitro studies by Mousson De Camaret et al. (2007) showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient. Sarzi et al. (2007) identified a homozygous N46S mutation in a patient (patient 9) with MTDPS3 who developed progressive liver disease at 2 months of age and had liver failure with cirrhosis at age 10 months. Autosomal Recessive Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 4 In a woman with features of MTDPS3, Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene: N46S and a 2-bp deletion in exon 5 (c.605_606delGA; 601465.0011), resulting in a frameshift and premature termination (Arg202TyrfsTer12). She presented in infancy with liver failure and underwent successful liver transplant at age 9 months. She was clinically well until age 20 years, when she developed acute myopathic episodes associated with increased serum creatine kinase and rhabdomyolysis; this latter phenotype was consistent with autosomal recessive progressive external ophthalmoplegia-4 (PEOB4; 617070). Noncirrhotic Portal Hypertension 1 In 3 patients from 2 unrelated consanguineous Turkish families with noncirrhotic portal hypertension-1 (NCPH1; 617068), Vilarinho et al. (2016) identified a homozygous N46S mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 894 control Turkish exomes. It was found at a very low frequency (3.134 x 10(-5)) in the ExAC database, only in the heterozygous state. Haplotype analysis suggested a founder effect. The findings significantly expanded the phenotype associated with the N46S mutation. (less)
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000297858.3
First in ClinVar: Aug 22, 2016 Last updated: Aug 07, 2021 |
Comment on evidence:
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson … (more)
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson De Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene: a c.137A-G transition (c.137A-G, NM_080916) in exon 1, resulting in an asn46-to-ser (N46S) substitution at a conserved residue in the P-loop domain, and a c.797T-G transversion in exon 6, resulting in a leu266-to-arg (L266R; 601465.0009) substitution in the C-terminal alpha-9 helix domain. The patient had a very unusual disease course: he presented in infancy with severe liver disease, but then had spontaneous improvement beginning at about 32 months of age. He showed normal development by 4 years of age and ultimately had almost complete reversal of the phenotype; he never had neurologic involvement. In vitro studies by Mousson De Camaret et al. (2007) showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient. Sarzi et al. (2007) identified a homozygous N46S mutation in a patient (patient 9) with MTDPS3 who developed progressive liver disease at 2 months of age and had liver failure with cirrhosis at age 10 months. Autosomal Recessive Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 4 In a woman with features of MTDPS3, Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene: N46S and a 2-bp deletion in exon 5 (c.605_606delGA; 601465.0011), resulting in a frameshift and premature termination (Arg202TyrfsTer12). She presented in infancy with liver failure and underwent successful liver transplant at age 9 months. She was clinically well until age 20 years, when she developed acute myopathic episodes associated with increased serum creatine kinase and rhabdomyolysis; this latter phenotype was consistent with autosomal recessive progressive external ophthalmoplegia-4 (PEOB4; 617070). Noncirrhotic Portal Hypertension 1 In 3 patients from 2 unrelated consanguineous Turkish families with noncirrhotic portal hypertension-1 (NCPH1; 617068), Vilarinho et al. (2016) identified a homozygous N46S mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 894 control Turkish exomes. It was found at a very low frequency (3.134 x 10(-5)) in the ExAC database, only in the heterozygous state. Haplotype analysis suggested a founder effect. The findings significantly expanded the phenotype associated with the N46S mutation. (less)
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Likely pathogenic
(Mar 31, 2016)
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no assertion criteria provided
Method: literature only
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Portal hypertension, noncirrhotic, 1
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784641.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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PORTAL HYPERTENSION, NONCIRRHOTIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001768710.3
First in ClinVar: Aug 07, 2021 Last updated: Jan 08, 2022 |
Comment on evidence:
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson … (more)
Mitochondrial DNA Depletion Syndrome 3 In a French boy with mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880) with hepatic involvement only (Ducluzeau et al., 2002), Mousson De Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene: a c.137A-G transition (c.137A-G, NM_080916) in exon 1, resulting in an asn46-to-ser (N46S) substitution at a conserved residue in the P-loop domain, and a c.797T-G transversion in exon 6, resulting in a leu266-to-arg (L266R; 601465.0009) substitution in the C-terminal alpha-9 helix domain. The patient had a very unusual disease course: he presented in infancy with severe liver disease, but then had spontaneous improvement beginning at about 32 months of age. He showed normal development by 4 years of age and ultimately had almost complete reversal of the phenotype; he never had neurologic involvement. In vitro studies by Mousson De Camaret et al. (2007) showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient. Sarzi et al. (2007) identified a homozygous N46S mutation in a patient (patient 9) with MTDPS3 who developed progressive liver disease at 2 months of age and had liver failure with cirrhosis at age 10 months. Autosomal Recessive Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions 4 In a woman with features of MTDPS3, Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene: N46S and a 2-bp deletion in exon 5 (c.605_606delGA; 601465.0011), resulting in a frameshift and premature termination (Arg202TyrfsTer12). She presented in infancy with liver failure and underwent successful liver transplant at age 9 months. She was clinically well until age 20 years, when she developed acute myopathic episodes associated with increased serum creatine kinase and rhabdomyolysis; this latter phenotype was consistent with autosomal recessive progressive external ophthalmoplegia-4 (PEOB4; 617070). Noncirrhotic Portal Hypertension 1 In 3 patients from 2 unrelated consanguineous Turkish families with noncirrhotic portal hypertension-1 (NCPH1; 617068), Vilarinho et al. (2016) identified a homozygous N46S mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 894 control Turkish exomes. It was found at a very low frequency (3.134 x 10(-5)) in the ExAC database, only in the heterozygous state. Haplotype analysis suggested a founder effect. The findings significantly expanded the phenotype associated with the N46S mutation. (less)
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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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Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. | Ronchi D | Brain : a journal of neurology | 2012 | PMID: 23043144 |
Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. | Dimmock DP | Human mutation | 2008 | PMID: 18205204 |
Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. | Sarzi E | The Journal of pediatrics | 2007 | PMID: 17452231 |
Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. | Mousson de Camaret B | The Biochemical journal | 2007 | PMID: 17073823 |
Progressive reversion of clinical and molecular phenotype in a child with liver mitochondrial DNA depletion. | Ducluzeau PH | Journal of hepatology | 2002 | PMID: 11983456 |
Text-mined citations for rs763615602 ...
HelpRecord last updated May 27, 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.