ClinVar Genomic variation as it relates to human health
NM_080916.3(DGUOK):c.211C>G (p.Pro71Ala)
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.
Uncertain significance(7); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_080916.3(DGUOK):c.211C>G (p.Pro71Ala)
Variation ID: 208752 Accession: VCV000208752.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 73938978 (GRCh38) [ NCBI UCSC ] 2: 74166105 (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 Dec 19, 2017 Mar 16, 2024 Jun 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_080916.3:c.211C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_550438.1:p.Pro71Ala missense NM_001318859.2:c.211C>G NP_001305788.1:p.Pro71Ala missense NM_001318860.2:c.-36-7741C>G intron variant NM_001318861.2:c.-37+6295C>G intron variant NM_001318862.2:c.-37+6295C>G intron variant NM_001318863.2:c.-36-7741C>G intron variant NM_080918.3:c.211C>G NP_550440.1:p.Pro71Ala missense NC_000002.12:g.73938978C>G NC_000002.11:g.74166105C>G NG_008044.1:g.17153C>G - Protein change
- P71A
- Other names
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- Canonical SPDI
- NC_000002.12:73938977:C: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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0.00200 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00044
Trans-Omics for Precision Medicine (TOPMed) 0.00047
Exome Aggregation Consortium (ExAC) 0.00077
1000 Genomes Project 0.00200
1000 Genomes Project 30x 0.00234
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 |
227 | 359 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 7, 2014 | RCV000190772.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2023 | RCV000482950.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2022 | RCV000727394.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 26, 2018 | RCV000779334.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2022 | RCV002500582.1 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 23, 2021 | RCV003955135.1 |
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
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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
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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Uncertain significance
(Oct 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000564933.3
First in ClinVar: Apr 29, 2017 Last updated: Dec 19, 2017 |
Comment:
The P71A variant in the DGUOK gene has been reported in the homozygous state in an individual with intellectual disability and spastic quadriplegia, but the … (more)
The P71A variant in the DGUOK gene has been reported in the homozygous state in an individual with intellectual disability and spastic quadriplegia, but the publication does not comment on the presence or absence of liver disease (Srivastava et al., 2014). The P71A variant is observed in 65/22564 (0.56%) alleles, although not in the homozygous state, from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The P71A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P71A as a variant of uncertain significance. (less)
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Uncertain significance
(Jun 07, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000708170.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Uncertain significance
(Jul 26, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915926.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The DGUOK c.211C>G (p.Pro71Ala) variant is a missense variant that has been reported in a homozygous state in one individual with mitochondrial DNA depletion syndrome, … (more)
The DGUOK c.211C>G (p.Pro71Ala) variant is a missense variant that has been reported in a homozygous state in one individual with mitochondrial DNA depletion syndrome, type 3 (Srivastava et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.014019 in the Iberian population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Pro71Ala variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial DNA depletion syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Aug 07, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244213.5
First in ClinVar: Sep 14, 2015 Last updated: Dec 19, 2017 |
Comment:
There is insufficient or conflicting evidence for classification of this alteration.
Number of individuals with the variant: 1
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Uncertain significance
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Portal hypertension, noncirrhotic, 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807020.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 21, 2022)
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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: SCV001483265.4
First in ClinVar: Mar 07, 2021 Last updated: Nov 11, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 71 of the DGUOK protein (p.Pro71Ala). … (more)
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 71 of the DGUOK protein (p.Pro71Ala). This variant is present in population databases (rs184770596, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 25131622). ClinVar contains an entry for this variant (Variation ID: 208752). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004021271.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: DGUOK c.211C>G (p.Pro71Ala) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four … (more)
Variant summary: DGUOK c.211C>G (p.Pro71Ala) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) 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 0.00088 in 251464 control chromosomes, predominantly at a frequency of 0.0046 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in DGUOK causing DGUOK-Related Disorders, allowing no conclusion about variant significance. c.211C>G has been reported in the literature in at least one homozygous individual affected with Mitochondrial DNA depletion syndrome, 3 (example: Srivastava_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25131622). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Dec 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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DGUOK-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004767444.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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 whole exome sequencing in child neurology practice. | Srivastava S | Annals of neurology | 2014 | PMID: 25131622 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DGUOK | - | - | - | - |
Text-mined citations for rs184770596 ...
HelpRecord last updated Mar 17, 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.