Submissions for variant NM_001605.3(AARS1):c.2251A>G (p.Arg751Gly) (rs143370729)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236870	SCV000292445	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	The R751G variant has been previously reported in two unrelated individuals who was homozygous for the variant (Simons et al., 2015). Functional studies show R751G impaired aminoacylation activity in vitro (Simons et al., 2015). R751G was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and an external database reports R751G was observed in 1/198 (0.5%) alleles from individuals from a population in the state of Utah. The R751G variant is a non-conservative amino acid substitution that alters a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae	RCV000556774	SCV000657669	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glycine at codon 751 of the AARS protein (p.Arg751Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs143370729, ExAC 0.009%). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 29653220). This variant has also been reported as compound heterozygous and homozygous in individuals with severe infantile epileptic encephalopathy, peripheral neuropathy, and deficient myelination (PMID: 25817015). ClinVar contains an entry for this variant (Variation ID: 190103). Experimental studies have shown that this missense change impairs the ability of the AARS protein to effectively catalyze aminoacylation (PMID: 25817015). 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	RCV000999715	SCV001156502	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
OMIM	RCV000170342	SCV000222750	pathogenic	Epileptic encephalopathy, early infantile, 29	2015-04-02	no assertion criteria provided	literature only