Submissions for variant NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)

gnomAD frequency: 0.00058  dbSNP: rs201431517

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000033047	SCV000245509	pathogenic	Combined oxidative phosphorylation defect type 15	2013-11-18	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory: once in trans with another pathogenic variant [S125L] in a 12-year-old female with mitochondrial disorder, Leigh disease, intellectual disability, short stature, microcephaly, PDA, brachydactyly, pes planus, congenital hypothyroidism; once homozygous in a 19-year-old male with static encephalopathy, optic atrophy, progressive spastic quadriparesis, elevated lactate, leukoencephalopathy. Variant pathogenic in recessive state; heterozygotes would be carriers.
GeneDx	RCV000320667	SCV000329428	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	This variant is reported to eliminate two exonic splicing enhancers and is predicted to cause skipping of exon 4, resulting in a frameshift and premature stop codon (R181SfsX5) (PMID: 21907147); Published functional studies demonstrate a damaging effect with reduced mitochondrial methionyl-tRNA formyltransferase protein activity (PMID: 25288793); This variant is associated with the following publications: (PMID: 24123792, 22499348, 27111573, 27290639, 24461907, 30911575, 31014978, 25911677, 26060307, 26968897, 26506407, 28058511, 25058219, 26633545, 23499752, 30569017, 30087118, 30369941, 31589614, 33146414, 34732400, 21907147, 25288793)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415235	SCV000492774	pathogenic	Short stature; Abnormal facial shape; Poor speech; Cytochrome C oxidase-negative muscle fibers; Inability to walk by childhood/adolescence; Decreased activity of mitochondrial complex I	2015-10-06	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000320667	SCV000511490	pathogenic	not provided	2016-08-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000320667	SCV000608722	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477042	SCV000894051	pathogenic	Combined oxidative phosphorylation defect type 15; Mitochondrial complex 1 deficiency, nuclear type 27	2022-01-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000033047	SCV001369202	pathogenic	Combined oxidative phosphorylation defect type 15	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. This variant was detected in homozygous state.
Invitae	RCV000320667	SCV001421026	pathogenic	not provided	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 209 of the MTFMT protein (p.Ser209Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201431517, gnomAD 0.07%). This missense change has been observed in individual(s) with combined OXPHOS deficiency and/or Leigh syndrome (PMID: 21907147, 22499348, 24461907, 25058219, 26060307, 27290639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg181Serfs5X. ClinVar contains an entry for this variant (Variation ID: 39827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTFMT protein function. Studies have shown that this missense change results in skipping of exon 4 and introduces a premature termination codon (PMID: 21907147, 25911677, 28058511). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000033047	SCV001448835	pathogenic	Combined oxidative phosphorylation defect type 15	2017-06-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000320667	SCV002017599	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000320667	SCV002064424	pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251943	SCV002523955	pathogenic	See cases	2021-04-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM3, PP3
DASA	RCV000033047	SCV002526406	pathogenic	Combined oxidative phosphorylation defect type 15	2022-06-10	criteria provided, single submitter	clinical testing	The c.626C>T;p.(Ser209Leu) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:39827; PMID: 24461907; 21907147; 22499348; 25058219; 27290639; 26060307) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 25911677, 28058511, 21907147) - PS3. The variant is present at low allele frequencies population databases (rs201431517– gnomAD 0.005715%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ser209Leu) was detected in trans with a Pathogenic variant (PMID: 24461907; 21907147; 22499348; 25058219; 27290639; 26060307) - PM3. In summary, the currently available evidence indicates that the variant is Pathogenic
Ambry Genetics	RCV002513312	SCV003683497	pathogenic	Inborn genetic diseases	2022-08-11	criteria provided, single submitter	clinical testing	The c.626C>T (p.S209L) alteration is located in exon 4 (coding exon 4) of the MTFMT gene. This alteration results from a C to T substitution at nucleotide position 626, causing the serine (S) at amino acid position 209 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.04% (102/280620) total alleles studied. The highest observed frequency was 0.07% (90/128424) of European (non-Finnish) alleles. This alteration has been detected in conjunction with a MTFMT pathogenic variant in multiple unrelated individuals with mitochondrial methionyl-tRNA formyltransferase deficiency. It has also been found to segregate among affected individuals in the same family (Haack, 2014; Tucker, 2011; Neveling, 2013). This amino acid position is well conserved in available vertebrate species. Functional studies show that this variant causes exon skipping in patient fibroblasts, which results in reduced MTFMT activity (Tucker, 2011). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000320667	SCV003802764	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	The MTFMT c.626C>T (p.Ser209Leu) missense variant results in the substitution of serine at amino acid position 209 with leucine. qRT-PCR studies in patient fibroblasts revealed that this variant is located in exon 4 and results in skipping of exon 4 causing a shift in the protein reading frame. This is predicted to result in a frameshift reported in the literature as p.Arg181SerfsTer6, and premature termination of the protein (PMID: 21907147; PMID: 30911575). Across a selection of the available literature, the c.626C>T variant has been identified in at least 10 individuals with Leigh syndrome spectrum (PMID: 30911575; PMID: 21907147). The highest frequency of this allele in the Genome Aggregation Database is 0.001059 in the European (non-Finnish) population (version 3.1.2). Functional studies demonstrated absence of MTFMT protein in patient fibroblasts, reduced levels of mitochondrially encoded polypeptides, and reduction in the assembly of complexes 1, IV and V. Additionally, patient fibroblasts exhibited severe defects in mitochondrial translation that could be rescued by exogenous expression of MTFMT (PMID: 21907147; PMID: 25911677; PMID: 30911575). The c.626C>T variant is the most common pathogenic allele in MTFMT and is a possible founder variant in the European population. Based on the available evidence, the c.626C>T (p.Ser209Leu) variant is classified as pathogenic for Leigh syndrome spectrum.
OMIM	RCV000033047	SCV000056827	pathogenic	Combined oxidative phosphorylation defect type 15	2014-03-01	no assertion criteria provided	literature only
Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)	RCV000190888	SCV000245762	pathogenic	Leigh syndrome	2015-06-08	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000033047	SCV000536791	pathogenic	Combined oxidative phosphorylation defect type 15	2016-06-23	no assertion criteria provided	research
OMIM	RCV000735417	SCV000863529	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 27	2014-03-01	no assertion criteria provided	literature only