Submissions for variant NM_139242.4(MTFMT):c.994C>T (p.Arg332Ter)

gnomAD frequency: 0.00011  dbSNP: rs200286768

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414310	SCV000490624	pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 58 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 34426522, 28058511, 22499348, 25058219, 23499752, 24461907, 27290639, 30369941, 31589614, 32577402, 32133637, 25911677, 31980526, 30911575)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000106390	SCV001367859	pathogenic	Combined oxidative phosphorylation defect type 15	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3.
Invitae	RCV000414310	SCV002166335	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg332*) in the MTFMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the MTFMT protein. This variant is present in population databases (rs200286768, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22499348, 23499752). 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: 39830). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002514139	SCV003681653	pathogenic	Inborn genetic diseases	2022-02-10	criteria provided, single submitter	clinical testing	The c.994C>T (p.R332*) alteration, located in exon 9 (coding exon 9) of the MTFMT gene, consists of a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 332. This alteration occurs at the 3' terminus of the MTFMT gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 14.65% of the protein. Premature stop codons are typically deleterious in nature. This alteration has been reported in the homozygous and compound heterozygous states in multiple patients with mitochondrial methionyl-tRNA formyltransferase deficiency (Bennett, 2020; Haack, 2012; Haack, 2014; Neeve, 2013; Pronicka, 2016; Theunissen, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000106390	SCV003807863	pathogenic	Combined oxidative phosphorylation defect type 15	2022-11-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PM2 supporting, PM3 strong
OMIM	RCV000033051	SCV000056831	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 27	2014-03-01	no assertion criteria provided	literature only
OMIM	RCV000106390	SCV000143894	pathogenic	Combined oxidative phosphorylation defect type 15	2014-03-01	no assertion criteria provided	literature only