Submissions for variant NM_018006.5(TRMU):c.1135G>T (p.Gly379Cys)

gnomAD frequency: 0.00002  dbSNP: rs773023974

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174140	SCV000225386	uncertain significance	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624682	SCV000742790	likely pathogenic	Inborn genetic diseases	2017-09-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000680154	SCV000807626	uncertain significance	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2017-09-01	criteria provided, single submitter	clinical testing	This variant was found once in our laboratory with another variant (A166E; phase undetermined) in a 2-month-old female with liver failure & metabolic acidosis. Heterozygotes would be expected to be asymptomatic carriers.
GeneDx	RCV000174140	SCV002097548	likely pathogenic	not provided	2024-11-20	criteria provided, single submitter	clinical testing	Published functional studies support this variant is associated with impaired mitochondrial protein synthesis (PMID: 38113276); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25326635, 28973083, 37184518, 38113276)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488423	SCV004240983	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: TRMU c.1135G>T (p.Gly379Cys) 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. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251018 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1135G>T has been reported in the literature with a second variant (c.497C>A; p.Ala166Glu) in at least one individual affected with Liver Failure Acute Infantile, Transient (e.g. Meng_2017). This report does not provide unequivocal conclusions about association of the variant with Liver Failure Acute Infantile, Transient. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28973083). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: two submitters classify the variant as likely pathogenic, and two submitters classify the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004754332	SCV005358476	likely pathogenic	TRMU-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The TRMU c.1135G>T variant is predicted to result in the amino acid substitution p.Gly379Cys. This variant was reported in the homozygous state or with a second TRMU variant in individuals with infantile liver failure (Meng et al 2017. PubMed ID: 28973083; Squires et al. 2023. PubMed ID: 37184518). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.