Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Human Genetics Munich, |
RCV000578402 | SCV000680187 | pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2017-11-08 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001564282 | SCV001787425 | pathogenic | not provided | 2019-05-29 | criteria provided, single submitter | clinical testing | 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) |
| Labcorp Genetics |
RCV001564282 | SCV003524665 | pathogenic | not provided | 2023-07-19 | criteria provided, single submitter | clinical testing | 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000578402 | SCV005203727 | pathogenic | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | 2024-07-03 | criteria provided, single submitter | clinical testing | 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. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV002252170 | SCV002523294 | uncertain significance | See cases | 2019-10-15 | flagged submission | clinical testing | ACMG classification criteria: PM2, PM3, PP3 |