Submissions for variant NM_004990.4(MARS1):c.1108T>C (p.Phe370Leu)

gnomAD frequency: 0.00001  dbSNP: rs140467171

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521595	SCV000617852	likely pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing	The F370L variant in the MARS gene has been reported previously, in trans with another missense variant, in an infant with failure to thrive, interstitial lung and liver disease, intermittent lactic acidosis, aminoaciduria, hypothyroidism, and transfusion-dependent anemia and motor delay. Functional studies showed that F370L significantly reduced the ability of MARS to couple methionine to its cognate tRNA, leading to 18% of wild type activity (vanMeel et al., 2013). The F370L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F370L 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. We interpret F370L as a likely pathogenic variant.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173433	SCV001336521	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004019069	SCV002755158	uncertain significance	not specified	2024-02-16	criteria provided, single submitter	clinical testing	The p.F370L variant (also known as c.1108T>C), located in coding exon 10 of the MARS gene, results from a T to C substitution at nucleotide position 1108. The phenylalanine at codon 370 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in one individual suspected of having Charcot-Marie-Tooth disease (Volodarsky M et al. J Med Genet, 2021 Apr;58:284-288). This variant was detected as compound heterozygous finding with another alteration in MARS in one individual whose multi-organ phenotype included lung and liver disease (van Meel E et al. BMC Med Genet, 2013 Oct;14:106). In an in vitro aminoacylation assay, this variant was found to significantly reduce the ability of MARS to couple methionine to its cognate tRNA (van Meel E et al. BMC Med Genet, 2013 Oct;14:106). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002514303	SCV003441140	uncertain significance	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U	2023-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 370 of the MARS protein (p.Phe370Leu). This variant is present in population databases (rs140467171, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MARS-related conditions (PMID: 24103465, 32376792). ClinVar contains an entry for this variant (Variation ID: 68463). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MARS function (PMID: 24103465). 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.
OMIM	RCV000059332	SCV000105910	pathogenic	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency	2013-10-08	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000709860	SCV000840193	not provided	MARS-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.