ClinVar Miner

Submissions for variant NM_004990.4(MARS1):c.1321T>C (p.Cys441Arg)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479825 SCV004223663 uncertain significance not specified 2023-11-10 criteria provided, single submitter clinical testing Variant summary: MARS1 c.1321T>C (p.Cys441Arg) results in a non-conservative amino acid change located in the Methionyl/Leucyl tRNA synthetase (IPR015413) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1321T>C in individuals affected with MARS1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003779193 SCV004604634 uncertain significance Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 441 of the MARS protein (p.Cys441Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MARS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

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