ClinVar Miner

Submissions for variant NM_001605.2(AARS1):c.1846C>T (p.Arg616Cys) (rs372221218)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001094472 SCV000398663 uncertain significance Charcot-Marie-Tooth disease, type 2N 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000653923 SCV000775813 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-04-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 616 of the AARS protein (p.Arg616Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372221218, ExAC 0.01%). This variant has not been reported in the literature in individuals with AARS-related disease. ClinVar contains an entry for this variant (Variation ID: 320335). 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: "Probably Damaging"; 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286056 SCV001472576 uncertain significance none provided 2020-01-09 criteria provided, single submitter clinical testing The AARS c.1846C>T; p.Arg616Cys variant (rs372221218), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 320335). This variant is found in the general population with a low overall allele frequency of 0.004% (11/282876 alleles) in the Genome Aggregation Database. The arginine at codon 616 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Arg616Cys variant is uncertain at this time.

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