Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485369 | SCV000568217 | pathogenic | not provided | 2017-01-09 | criteria provided, single submitter | clinical testing | 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. |
| Invitae | RCV000485369 | SCV003524725 | pathogenic | not provided | 2023-12-30 | criteria provided, single submitter | clinical testing | 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. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000008633 | SCV003807395 | pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2022-07-25 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM3 moderated |
| Revvity Omics, |
RCV000485369 | SCV003827548 | pathogenic | not provided | 2021-12-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004528095 | SCV004029856 | pathogenic | DGUOK-related disorder | 2023-07-25 | criteria provided, single submitter | clinical testing | 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. |
| Center for Genomic Medicine, |
RCV000008633 | SCV004805422 | likely pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2024-03-25 | criteria provided, single submitter | research | |
| OMIM | RCV000008633 | SCV000028842 | pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2002-09-01 | no assertion criteria provided | literature only | |
| Biochemical Molecular Genetic Laboratory, |
RCV000008633 | SCV001133206 | pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2019-09-26 | no assertion criteria provided | clinical testing |