Submissions for variant NM_001605.3(AARS1):c.310T>C (p.Trp104Arg)

gnomAD frequency: 0.00001  dbSNP: rs1057520616

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424967	SCV000516601	uncertain significance	not provided	2016-05-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the AARS gene. The W104R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W104R 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, 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	RCV001298338	SCV001487390	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-03-27	criteria provided, single submitter	clinical testing	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. 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 104 of the AARS protein (p.Trp104Arg). This variant is not present in population databases (gnomAD no frequency). 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: 379487).
Ambry Genetics	RCV004022315	SCV004914685	uncertain significance	Inborn genetic diseases	2023-11-27	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.310T>C (p.W104R) alteration is located in exon 3 (coding exon 2) of the AARS gene. This alteration results from a T to C substitution at nucleotide position 310, causing the tryptophan (W) at amino acid position 104 to be replaced by an arginine (R). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the AARS c.310T>C alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.W104 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.W104R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.