Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000526485 | SCV000639555 | uncertain significance | Charcot-Marie-Tooth disease, dominant intermediate C | 2017-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine with arginine at codon 496 of the YARS protein (p.Lys496Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs768160751, ExAC 0.009%) but has not been reported in the literature in individuals with a YARS-related disease. 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 arginine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |