ClinVar Miner

Submissions for variant NM_004990.4(MARS1):c.1945A>G (p.Asn649Asp)

gnomAD frequency: 0.00003  dbSNP: rs748955220
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000811670 SCV000951948 uncertain significance Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 649 of the MARS protein (p.Asn649Asp). This variant is present in population databases (rs748955220, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 655481). 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. 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.
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173425 SCV001336513 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Ambry Genetics RCV003323728 SCV003887546 uncertain significance not specified 2023-01-10 criteria provided, single submitter clinical testing The c.1945A>G (p.N649D) alteration is located in exon 15 (coding exon 15) of the MARS gene. This alteration results from a A to G substitution at nucleotide position 1945, causing the asparagine (N) at amino acid position 649 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323728 SCV004028905 uncertain significance not specified 2023-07-06 criteria provided, single submitter clinical testing Variant summary: MARS c.1945A>G (p.Asn649Asp) results in a conservative amino acid change located in the Methionyl/Leucyl tRNA synthetase domain (IPR015413) of 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 3.6e-05 in 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1945A>G has not been reported in the literature in individuals affected with MARS1-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32376792). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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