Submissions for variant NM_018006.5(TRMU):c.1142G>A (p.Gly381Glu)

dbSNP: rs774047684

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001150926	SCV001312021	uncertain significance	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002557253	SCV003012583	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with glutamic acid at codon 381 of the TRMU protein (p.Gly381Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs774047684, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of TRMU-related conditions (PMID: 33485800). ClinVar contains an entry for this variant (Variation ID: 903538). 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 TRMU protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003473718	SCV004204378	likely pathogenic	Aminoglycoside-induced deafness	2023-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001150926	SCV005202551	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: TRMU c.1142G>A (p.Gly381Glu) results in a non-conservative amino acid change located in the tRNA-specific 2-thiouridylase MnmA-like, C-terminal domain (IPR046885) 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 4e-06 in 251030 control chromosomes. c.1142G>A has been reported in the literature in at least two compound heterozygous individuals affected with Liver Failure Acute Infantile, Transient (Alves_2020, Murali_2021, Martin-Saavedra_2022, Vogel_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Liver Failure Acute Infantile, Transient. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in residual enzymatic activity of the mutant protein in in vitro cell-based assays (Ahmad_2024). ClinVar contains an entry for this variant (Variation ID: 903538). Based on the evidence outlined above, the variant was classified as likely pathogenic.