ClinVar Miner

Submissions for variant NM_004990.4(MARS1):c.734A>G (p.Glu245Gly)

gnomAD frequency: 0.00007  dbSNP: rs778753999
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000512787 SCV000608652 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Invitae RCV001225087 SCV001397323 uncertain significance Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 245 of the MARS protein (p.Glu245Gly). This variant is present in population databases (rs778753999, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 444297). 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 glycine 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.
Ambry Genetics RCV003235261 SCV003697559 likely benign not specified 2021-08-30 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235261 SCV003933790 uncertain significance not specified 2023-05-24 criteria provided, single submitter clinical testing Variant summary: MARS c.734A>G (p.Glu245Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251494 control chromosomes. To our knowledge, no occurrence of c.734A>G in individuals affected with MARS1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as: VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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