Submissions for variant NM_017819.4(TRMT10C):c.775_778del (p.Val259fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV002465009	SCV002759401	likely pathogenic	Combined oxidative phosphorylation defect type 30	2022-06-13	criteria provided, single submitter	clinical testing	The c.775_778del variant was identified as a part of carrier screening. This variant is not present in publicly available population databases like 1000 Genomes, EVS and Indian Exome Database. The heterozygous state of the variant is present in ExAC and gnomAD, at a low frequency. The variant is not present in our in-house exome database. The variant was not reported to ClinVar, Human Genome mutation database (HGMD) or OMIM databases, in any affected individuals. In-silico pathogenicity prediction programs like MutationTaster2, CADD, Varsome etc. predicted this variant to be likely deleterious. The variant causes frameshift at the 259th amino acid position of the wild-type transcript that creates a premature stopcodon at the 270th amino acid position fo the altered transcript that either results in creating a truncated protein or causes nonsense mediated decay of the mRNA.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002573561	SCV003505383	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	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. This variant has not been reported in the literature in individuals affected with TRMT10C-related conditions. This variant is present in population databases (rs780421288, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Val259Asnfs*12) in the TRMT10C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 145 amino acid(s) of the TRMT10C protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331369	SCV004037849	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: RG9MTD1 or TRMT10C c.775_778delGTTA (p.Val259AsnfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein, however current evidence is not sufficient to establish loss-of-function variants in RG9MTD1 as causative of disease. The variant allele was found at a frequency of 3.2e-05 in 280742 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.775_778delGTTA in individuals affected with Combined Oxidative Phosphorylation Defect Type 30 and no experimental evidence demonstrating its impact on protein function have been reported. 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 uncertain significance.