Submissions for variant NM_004990.4(MARS1):c.1852C>T (p.Arg618Cys) (rs587777718)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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.
OMIM	RCV000144083	SCV000189158	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2u	2013-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000192267	SCV000239915	pathogenic	Charcot-Marie-Tooth disease	2015-04-30	no assertion criteria provided	literature only
Hadassah Hebrew University Medical Center	RCV000677354	SCV000692464	likely pathogenic	Interstitial lung and liver disease		no assertion criteria provided	clinical testing