Submissions for variant NM_018006.5(TRMU):c.680G>C (p.Arg227Thr)

gnomAD frequency: 0.00002  dbSNP: rs764622793

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001879773	SCV002246212	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 227 of the TRMU protein (p.Arg227Thr). This variant is present in population databases (rs764622793, gnomAD 0.01%). This missense change has been observed in individual(s) with transient infantile liver failure (PMID: 28973083, 30740308, 33365252). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 973463). 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 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	RCV002298915	SCV002598916	uncertain significance	not specified	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: TRMU c.680G>C (p.Arg227Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251470 control chromosomes (gnomAD). c.680G>C has been reported in the literature as a biallelic genotype in individuals affected with Liver Failure Acute Infantile, Transient (example, Meng_2017 cited in Soler-Alfanso_2019, Sala-Coromina_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28973083, 33485800, 33365252, 30740308, 36305855). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003473836	SCV004204370	pathogenic	Aminoglycoside-induced deafness	2023-07-23	criteria provided, single submitter	clinical testing
Elsea Laboratory, Baylor College of Medicine	RCV001250083	SCV001424255	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2020-04-01	no assertion criteria provided	clinical testing