ClinVar Miner

Submissions for variant NM_001605.2(AARS1):c.2186G>A (p.Arg729Gln) (rs142850278)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236790 SCV000293369 uncertain significance not provided 2016-07-29 criteria provided, single submitter clinical testing The R729Q has been reported in an individual with an inherited neuropathy, however it was also reported in control individuals (Schabhüttl et al., 2014). 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 R729Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is 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 RCV000704888 SCV000833860 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-05-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 729 of the AARS protein (p.Arg729Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142850278, ExAC 0.03%), 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: 246063). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000765312 SCV000896567 uncertain significance Charcot-Marie-Tooth disease, type 2N; Epileptic encephalopathy, early infantile, 29 2018-10-31 criteria provided, single submitter clinical testing

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