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

gnomAD frequency: 0.00004  dbSNP: rs143370729

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236870	SCV000292445	likely pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33317386, 26670257, 25817015, 27159321, 31775912, 33294374, 34446925, 32376792, 34490615, 29653220)
Invitae	RCV000556774	SCV000657669	pathogenic	Charcot-Marie-Tooth disease type 2	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 751 of the AARS protein (p.Arg751Gly). This variant is present in population databases (rs143370729, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive epileptic encephalopathy (PMID: 25817015, 33294374). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 29653220); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 190103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AARS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AARS function (PMID: 25817015). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000999715	SCV001156502	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000236870	SCV002051583	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing	BS1, PS3_Supporting, PP3, PM1
Ambry Genetics	RCV002460950	SCV002755352	uncertain significance	Inborn genetic diseases	2022-05-19	criteria provided, single submitter	clinical testing	The p.R751G variant (also known as c.2251A>G), located in coding exon 15 of the AARS gene, results from an A to G substitution at nucleotide position 2251. The arginine at codon 751 is replaced by glycine, an amino acid with dissimilar properties. This alteration was detected in an individual among a cohort of Charcot-Marie-Tooth disease patients (Vaeth S et al. Eur J Med Genet, 2019 Jan;62:1-8). Furthermore, functional studies showed reduced aminoacylation activity in vitro (Simons C et al. Am J Hum Genet, 2015 Apr;96:675-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. However, based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335174	SCV004046330	likely pathogenic	AARS-related disorders		criteria provided, single submitter	clinical testing	This variant has been previously reported in heterozygous, compound heterozygous or homozygous state in patients with AARS-related disorders (PMID: 25817015, 33294374, 29653220). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/282822) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Experimental studies have shown that this variant reduces the normal function of the AARS protein (PMID: 25817015). Based on the available evidence, the c.2251A>G (p.Arg751Gly) variant is classified as Likely Pathogenic.
OMIM	RCV000170342	SCV000222750	pathogenic	Developmental and epileptic encephalopathy, 29	2015-04-02	no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003311704	SCV004011913	uncertain significance	Charcot-Marie-Tooth disease axonal type 2N	2017-04-20	no assertion criteria provided	literature only