Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226829 | SCV003923119 | likely pathogenic | Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins | 2023-03-30 | criteria provided, single submitter | clinical testing | Variant summary: TRMU c.1099C>T (p.Gln367X) results in a premature termination codon, located in exon 10 (i.e. the penultimate exon), and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a large part of the 421 amino acid long protein, which affects the C-terminal domain (amino acid 303-383; IPR046885). This variant is also located close to the canonical splice-site, and 4/4 computational tools predict no significant impact on normal splicing. Although, these predictions have yet to be confirmed by functional studies. A splice variant downstream from our position is reported in a patient, who carried a pathogenic missense variant in trans, and RNA analysis indicated that this variant leads to a frameshift with an altered sequence in the last exon and a premature stop codon in ~50% of the transcripts (PMID 21931168). This report might indicate a clinical importance for the deleted protein region. The variant was absent in 251016 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1099C>T in individuals affected with Liver Failure Acute Infantile, Transient and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |