ClinVar Miner

Submissions for variant NM_018006.5(TRMU):c.706-1G>A

dbSNP: rs778799889
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001390441 SCV001592179 pathogenic not provided 2023-10-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the TRMU gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TRMU are known to be pathogenic (PMID: 19732863, 23625533). This variant is present in population databases (rs778799889, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with acute infantile liver failure (PMID: 19732863). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1076499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001801250 SCV002600312 pathogenic Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins 2022-10-05 criteria provided, single submitter clinical testing Variant summary: TRMU c.706-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 3' acceptor site and three also predict the variant creates/strengthens a cryptic exonic 3' acceptor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in exon skipping (e.g. Zeharia_2009). The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes (gnomAD). c.706-1G>A has been reported in the literature as a compound heterozygous genotype in at least one individual affected with acute infantile liver failure (e.g. Zeharia_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV001801250 SCV000021505 pathogenic Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins 2009-09-01 no assertion criteria provided literature only
Natera, Inc. RCV001801250 SCV002076155 pathogenic Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins 2021-02-04 no assertion criteria provided clinical testing

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