Submissions for variant NM_080916.3(DGUOK):c.444-62C>A

dbSNP: rs528587600

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001909174	SCV002174152	likely pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the DGUOK gene. It does not directly change the encoded amino acid sequence of the DGUOK protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 20 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 19394258; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1403676). Studies have shown that this variant results in the activation of a cryptic splice site in intron 3 (PMID: 19394258). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587246	SCV005076233	pathogenic	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	2024-04-15	criteria provided, single submitter	clinical testing	Variant summary: DGUOK c.444-62C>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Brahimi_2009). The variant was absent in 250954 control chromosomes (gnomAD). c.444-62C>A has been reported in the literature in multiple individuals affected with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver (Brahimi_2009). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 19394258). ClinVar contains an entry for this variant (Variation ID: 1403676). Based on the evidence outlined above, the variant was classified as pathogenic.