Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000478608 | SCV000568853 | uncertain significance | not provided | 2017-03-03 | criteria provided, single submitter | clinical testing | The R618C variant in the MARS gene has been reported previously in the heterozygous state in a male individual and his maternal uncle, both of whom had late-adult onset of peripheral axonal neuropathy classified as Charcot-Marie-Tooth disease type 2U (CMT2U); however, this variant was also observed in the individual's unaffected mother (Gonzalez et al., 2013). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R618C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies demonstrated that the R618C variant did not rescue growth of yeast deficient in an ortholog of MARS (Gonzales et al., 2013). However, additional studies are needed to validate the functional effect of this variant in vivo. We interpret R618C as a variant of uncertain significance. |
| Molecular Genetics Laboratory, |
RCV000192267 | SCV001336525 | uncertain significance | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV002512554 | SCV003517163 | uncertain significance | Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency; Charcot-Marie-Tooth disease axonal type 2U | 2023-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 618 of the MARS protein (p.Arg618Cys). This variant is present in population databases (rs587777718, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal dominant MARS-related conditions and/or autosomal recessive MARS-related conditions (PMID: 23729695, 29655802). ClinVar contains an entry for this variant (Variation ID: 156025). 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. Experimental studies have shown that this missense change affects MARS function (PMID: 23729695, 29655802). 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. |
| OMIM | RCV000144083 | SCV000189158 | pathogenic | Charcot-Marie-Tooth disease axonal type 2U | 2013-11-01 | no assertion criteria provided | literature only | |
| Hadassah Hebrew University Medical Center | RCV000677354 | SCV000692464 | likely pathogenic | Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency | no assertion criteria provided | clinical testing |