Submissions for variant NM_139242.4(MTFMT):c.669G>T (p.Leu223Phe)

dbSNP: rs372732702

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480605	SCV000565247	likely pathogenic	not provided	2014-07-07	criteria provided, single submitter	clinical testing	A novel L223F variant that is likely pathogenic was identified in the MTFMT gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The L223F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae	RCV000480605	SCV003484273	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 223 of the MTFMT protein (p.Leu223Phe). This variant is present in population databases (rs372732702, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with MTFMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 418337). 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. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000480605	SCV001549520	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MTFMT p.Leu223Phe variant was not identified in the literature nor was it identified in the Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs372732702) and ClinVar (reported as likely pathogenic by GeneDx). The variant was identified in control databases in 30 of 232006 chromosomes at a frequency of 0.000129 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 18 of 9516 chromosomes (freq: 0.001892), Latino in 10 of 31840 chromosomes (freq: 0.000314) and European (non-Finnish) in 2 of 106386 chromosomes (freq: 0.000019), but was not observed in the African, East Asian, European (Finnish), Other, and South Asian populations. The p.Leu223 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.