Submissions for variant NM_017819.4(TRMT10C):c.542G>T (p.Arg181Leu)

gnomAD frequency: 0.00013  dbSNP: rs199730889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252056	SCV002523624	likely pathogenic	See cases	2020-04-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586627	SCV005077343	uncertain significance	not specified	2024-04-05	criteria provided, single submitter	clinical testing	Variant summary: RG9MTD1 c.542G>T (p.Arg181Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. c.542G>T has been reported in the literature in two individuals affected with birth-onset multiple respiratory chain deficiencies via WES (Metodiev_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Decreased protein levels of RG9MTD1, an increase in mt-RNA precursors and defective mitochondrial protein synthesis were found using fibroblasts from the patient carrying the homozygous variant (Metodiev_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27132592). ClinVar contains an entry for this variant (Variation ID: 224316). The gene-disease association of RG9MTD1 and Combined Oxidative Phosphorylation Defect Type 30 has not been fully established. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791330	SCV005413604	likely pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	BP4, PP4, PM2_moderate, PM3_strong
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000754100	SCV000264779	pathogenic	Mitochondrial disease	2016-03-08	no assertion criteria provided	clinical testing
OMIM	RCV000225227	SCV000282033	pathogenic	Combined oxidative phosphorylation defect type 30	2019-09-10	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758673	SCV005361491	pathogenic	TRMT10C-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The TRMT10C c.542G>T variant is predicted to result in the amino acid substitution p.Arg181Leu. This variant has been reported in the homozygous and compound heterozygous state in three unrelated individuals presenting at birth with lactic acidosis, hypotonia, feeding difficulties, deafness, and brain abnormalities consistent with combined oxidative phosphorylation deficiency (Metodiev et al. 2016. PubMed ID: 27132592; Camelo et al. 2021. PubMed ID: 33886802). Patient derived fibroblast cell lines exhibited decreased MRPP1 (TRMT10C protein) levels, impaired mt-tRNA processing and defective mitochondrial protein synthesis, which was rescued by introduction of wild-type TRMT10C (Metodiev et al. 2016. PubMed ID: 27132592). This variant is reported in 0.034% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.