ClinVar Miner

Submissions for variant NM_001605.2(AARS1):c.385C>G (p.Pro129Ala) (rs370622071)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236492 SCV000293675 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing The P129A 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 nor with any significant frequency in the 1000 Genomes Project. The P129A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, Alanine is observed at this position in evolution. In silico analysis predicts this variant is probably 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.
Invitae RCV000653927 SCV000775817 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 129 of the AARS protein (p.Pro129Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs370622071, ExAC 0.02%), 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 AARS-related disease. ClinVar contains an entry for this variant (Variation ID: 246216). 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: "Benign"; Align-GVGD: "Class C0"). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660586 SCV000782698 uncertain significance Epileptic encephalopathy, early infantile, 29 2017-07-05 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000999718 SCV001156505 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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