Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001217570 | SCV001389416 | uncertain significance | Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U | 2023-02-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Pro220Leufs*25) in the MARS gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MARS cause disease. This variant is present in population databases (rs777370844, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 946663). 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 | RCV003363176 | SCV004078702 | pathogenic | Inborn genetic diseases | 2023-07-21 | criteria provided, single submitter | clinical testing | The c.659delC (p.P220Lfs*25) alteration, located in exon 6 (coding exon 6) of the MARS gene, consists of a deletion of one nucleotide at position 659, causing a translational frameshift with a predicted alternate stop codon after 25 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of MARS has been associated with autosomal recessive (AR) cytoplasmic methionine-tRNA synthetase deficiency, haploinsufficiency of MARS has not been established as a mechanism of disease for autosomal dominant (AD) MARS1-related Charcot-Marie-Tooth disease, type 2. Based on the available evidence, the MARS c.659delC (p.P220Lfs*25) alteration is classified as pathogenic for AR cytoplasmic methionine-tRNA synthetase deficiency; however, the clinical significance for AD MARS1-related Charcot-Marie-Tooth disease, type 2 is uncertain. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. |