Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000203886 | SCV000260521 | uncertain significance | Charcot-Marie-Tooth disease, dominant intermediate C | 2019-05-28 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with alanine at codon 524 of the YARS protein (p.Gly524Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs201687117, ExAC 0.005%). This variant has not been reported in the literature in individuals with YARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 220175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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. |
Gene |
RCV000523644 | SCV000620226 | uncertain significance | not provided | 2017-08-28 | criteria provided, single submitter | clinical testing | The G524A variant in the YARS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 3/66,476 alleles (0.0045%) from individuals of non-Finnish European background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). The G524A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, a missense variant in a neighboring residue (G525R) has been reported in the Human Gene Mutation Database in association with an autosomal recessive YARS-related disorder (Stenson et al., 2014). We interpret G524A as a variant of uncertain significance. |
Fulgent Genetics, |
RCV000203886 | SCV000896354 | uncertain significance | Charcot-Marie-Tooth disease, dominant intermediate C | 2018-10-31 | criteria provided, single submitter | clinical testing |