ClinVar Miner

Submissions for variant NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)

gnomAD frequency: 0.00011  dbSNP: rs141340466
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001057120 SCV001221596 likely benign Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U 2024-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV003987472 SCV002754940 likely benign not specified 2020-07-07 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 RCV003987472 SCV004804445 uncertain significance not specified 2024-01-11 criteria provided, single submitter clinical testing Variant summary: MARS1 c.1177G>A (p.Ala393Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282896 control chromosomes (gnomAD). c.1177G>A has been reported in the literature in individuals affected with pulmonary alveolar proteinosis or Charcot-Marie-Tooth disease without strong evidence of causality (Hadchouel_2015, La Fay_2021, Nam_2022). These reports do not provide unequivocal conclusions about association of the variant with MARS1-Related Disorders. Publications report experimental evidence evaluating an impact on protein function (Hadchouel_2015, Comiso_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 25913036, 29775242, 34496286, 34813128). ClinVar contains an entry for this variant (Variation ID: 242615). Based on the evidence outlined above, the variant was classified as uncertain significance.

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