Submissions for variant NM_018006.5(TRMU):c.697C>T (p.Leu233Phe)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004702107	SCV005201864	likely pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 19732863, 36305855, 33205917, 23625533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702106	SCV005205335	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: TRMU c.697C>T (p.Leu233Phe) results in a non-conservative amino acid change located in the tRNA-specific 2-thiouridylase MnmA-like, central domain (IPR046884) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes. c.697C>T has been reported in the literature in a presumed compound heterozygous individual and in a homozygous individual affected with Liver Failure Acute Infantile, Transient (e.g. Zeharia_2009, Gaignard_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 20%-<30% of normal activity in an in vitro cell assay due to impaired mutant protein stability (Ahmad_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38113276, 23625533, 19732863). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.