Submissions for variant NM_001605.3(AARS1):c.1399A>G (p.Ile467Val)

gnomAD frequency: 0.00006  dbSNP: rs376215607

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444413	SCV000535744	uncertain significance	not provided	2017-01-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the AARS gene. The I467V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I467V 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). This substitution occurs at a position that is conserved across species. However, the I467V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553492	SCV000657657	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 467 of the AARS protein (p.Ile467Val). This variant is present in population databases (rs376215607, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 392470). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AARS protein function with a negative predictive value of 95%. 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	RCV004022515	SCV004916920	uncertain significance	Inborn genetic diseases	2024-02-26	criteria provided, single submitter	clinical testing	The c.1399A>G (p.I467V) alteration is located in exon 11 (coding exon 10) of the AARS gene. This alteration results from a A to G substitution at nucleotide position 1399, causing the isoleucine (I) at amino acid position 467 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.