ClinVar Miner

Submissions for variant NM_001605.3(AARS1):c.1764G>C (p.Gln588His)

gnomAD frequency: 0.00001  dbSNP: rs771478786
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002236880 SCV002510194 uncertain significance Charcot-Marie-Tooth disease type 2 2024-10-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 588 of the AARS protein (p.Gln588His). This variant is present in population databases (rs771478786, gnomAD 0.01%). 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: 1682202). 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 RCV002463174 SCV002756420 uncertain significance Inborn genetic diseases 2020-12-30 criteria provided, single submitter clinical testing The p.Q588H variant (also known as c.1764G>C), located in coding exon 12 of the AARS gene, results from a G to C substitution at nucleotide position 1764. The glutamine at codon 588 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie-Tooth disease, axonal, type 2N (CMT2N); however, its contribution to the development of AARS-related early infantile epileptic encephalopathy (EIEE) is uncertain.

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