ClinVar Miner

Submissions for variant NM_001605.2(AARS1):c.2222C>T (p.Thr741Met) (rs148383122)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236072 SCV000293574 uncertain significance not provided 2015-11-19 criteria provided, single submitter clinical testing The T741M 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 with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however it was observed in 1/188 (0.53%) Columbian alleles in the 1000 Genomes Project. The T741M 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position, where amino acids with similar properties to Threonine are tolerated across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000548635 SCV000657668 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 741 of the AARS protein (p.Thr741Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs148383122, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with an AARS-related disease. ClinVar contains an entry for this variant (Variation ID: 246148). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on AARS function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000999714 SCV001156501 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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