ClinVar Miner

Submissions for variant NM_001605.3(AARS1):c.1244A>G (p.Tyr415Cys)

gnomAD frequency: 0.00003  dbSNP: rs373069396
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441580 SCV000529289 uncertain significance not provided 2020-01-22 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000653855 SCV000775745 uncertain significance Charcot-Marie-Tooth disease type 2 2025-01-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 415 of the AARS protein (p.Tyr415Cys). This variant is present in population databases (rs373069396, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. 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: 387319). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AARS protein function. 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 RCV002461167 SCV002755271 uncertain significance Inborn genetic diseases 2021-01-14 criteria provided, single submitter clinical testing The p.Y415C variant (also known as c.1244A>G), located in coding exon 9 of the AARS gene, results from an A to G substitution at nucleotide position 1244. The tyrosine at codon 415 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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