Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623160 | SCV000741235 | uncertain significance | Inborn genetic diseases | 2022-06-16 | criteria provided, single submitter | clinical testing | The c.1573C>T (p.R525W) alteration is located in exon 17 (coding exon 17) of the QARS gene. This alteration results from a C to T substitution at nucleotide position 1573, causing the arginine (R) at amino acid position 525 to be replaced by a tryptophan (W). The amino acid is located in a functionally important protein domain:_x000D_ The p.R525W amino acid is located in the catalytic domain which is responsible for the ATP dependent attachment of the amino acid to the enzyme. It is located after the KMSKS motif which binds to ATP. Another missense substitution in the same loop (p.R515Y) was suggested to increase the aggregation of this protein and disrupt aminoacylation activity. However, there is no evidence protein aggregation and function would be affected by a change in position p.R525._x000D_ _x000D_ Structual modeling of this alteration is inconclusive_x000D_ Structural modeling performed in house at Ambry Genetics revealed that the position R525 is in a disordered loop lying in a buried region between the catalytic domain and the codon binding domain. This interfacial is identified to be subject to allosteric effects by (Zhang, 2014). The change R->W is unfavored (BLOSUM62 -3 and the nearby variant (R215W) has been identified to be pathogenic. However, R525W is not significantly destabilizing (-0.35) compared to R215W (10.52). While the variant likely perturbs in folding, structural evidence is not conclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001303875 | SCV001493137 | uncertain significance | Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome | 2021-05-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 525 of the QARS protein (p.Arg525Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 520898). 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: "Not Available"; Align-GVGD: "Class C65"). 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. |