Table.3.
Evaluation of genetic variants in LeuRS.
| Variant and amino acid change (NM_015340.3) | Effect † | Stability + | ClinVar | Deafness Variation Database/LOVD | Hearing loss expert panel classification + Modeling | Reference |
|---|---|---|---|---|---|---|
|
c.351G > C; p.(Met117Ile) |
Stability | 4.11 ± 0.63 | – | P/LP |
Likely Pathogenic (PM2, PM3, PP1, PP4,PP3) |
PMID: 26,970,254 |
|
c.371A > T; p.(Asn124Ile) |
Non conclusive | 0.41 ± 0.66 | P | P/– |
Likely Pathogenic (PM2, PM3_Strong, PP4) |
PMID: 28,708,303 |
| c.440A > C; p.(Gln147Pro) | Stability | 1.49 ± 0.12 | LP | LP/– |
Likely Pathogenic (PM2, PM3, PP4, BP4_Supporting, PP3) |
SCV000994657.1 |
| c.457A > C; p.(Asn153His) | Stability | 3.36 ± 0.82 | LP | LP/– |
Likely Pathogenic (PM2, PM3 PP3, PP4) |
PMID: 32,423,379 |
| c.683G > A p.(Arg228His) | Electrostatic Surface | 0.40 ± 0.02 | LP | LP/LP |
Likely Pathogenic (PM2, PM3_Supporting, PP3, PP4) |
PMID: 28,000,701 |
| c.880G > A; p.(Glu294Lys) | Electrostatic surface | 0.67 ± 0.14 | – | P/LP |
Likely Pathogenic (PM2, PM3_Strong, PP4, PP3) |
PMID: 28,000,701; 3,276,773; 29,205,794 |
| c.899C > T; p.(Thr300Met) | tRNA interaction | 0.12 ± 0.84 | P | P/P |
Likely Pathogenic (PM2, PM3, PP1, PP3, PP4) |
PMID: 26,657,938 |
| c.1077del; p.Ile360fs | LoF | – | P | P/P |
Pathogenic (PVS1, PS3_Supporting, PM2, PM3, PP4) |
PMID: 23,541,342 |
| c.1115C > G; p.(Ser372*) | LoF | – | LP | LP/– |
Pathogenic (PVS1, PM2, PP4) |
SCV000891207.1 |
| c.1237G > A; p.(Glu413Lys) | Electrostatic surface | 0.14 ± 0.02 | LP | LP/– |
VUS (PM2, BP4, PP4) |
SCV001244305.1 |
| c.1358G > A; p.(Arg453Gln) | Electrostatic surface/Stability? | 1.42 ± 0.3 | – | P/P |
Likely Pathogenic (PM2_Supporting, PM3, PP3, PP4) |
PMID: 27,650,058 |
| c.1481dup; p.(Leu495fs) | LoF | – | – | P/– |
Pathogenic (PVS1, PM2, PM3, PP1_Supporting) |
This study paper |
| c.1520C > G; p.(Pro507Arg) | Stability | 2.20 ± 0.07 | LP | LP/– |
Likely Pathogenic (PM2, PM3, PP1_Supporting, PP3) |
SCV000731430.1 |
| c.1556C > T; p.(Thr519Met) | & | − 0.44 ± 0.25 | – | P/– |
Likely Pathogenic (PM2, PM3, PP1_Supporting, PP3, PP4) |
PMID: 29,205,794 |
| c.1565C > A; p.Thr522Asn | & | − 0.59 ± 0.08 | LP | P/LP |
Likely Pathogenic (PM2_Supporting, PM3_Strong, PS3_Supporting, PP3, PP4) |
PMID: 23,541,342 |
| c.1607C > T; p.(Pro536Leu) | Stability | 6.82 ± 1.87 | LP | LP/– |
Likely Pathogenic (PM2, PS3_Supporting, PM3, PP3, PP4) |
Accession: SCV000994658.1 |
| c.1886C > T; p.Thr629Met | Stability | 2.56 ± 0.19 | P | P/P |
Likely Pathogenic (PM2, PM3_Strong, PP1_Sup, PP4) |
PMID: 23,541,342 |
| c.1912G > A; p.(Glu638Lys) | tRNA interaction | − 0.06 ± 0.50 | P | P/P |
Likely Pathogenic (PM2, PM3, PP1_Supporting, PP3, PP4) |
PMID: 26,657,938 |
| c.1987C > T; p.(Arg663Trp) | Stability | 2.94 ± 0.32 | P | P/– |
Likely Pathogenic (PM2, PS3_Supporting, PM3_Strong, PP3, PP4) |
PMID: 28,708,303 |
| c.2108T > C; p.(Ile703Thr) | tRNA interaction | 0.67 ± 0.11 | – | LP/– |
Likely Pathogenic (PM2, PM3, PP3, PP4) |
PMID: 32,767,731 |
†Classification of variants according to structural criteria. + ΔΔG Energy evaluation for pathogenic and likely pathogenic genetic variants, FOLDX: |X|± SD (n = 5). LoF loss of function, P pathogenic, LP: likely pathogenic. This information was compiled from the LOVD3, ClinVar and deafness variation databases until 26 January 2021. &: both residues are oriented facing the core, causing a probable steric effect. The new model of LeuRS was considered a new parameter (PP3 score applied) to classify the variants reported in databases according to the Hearing Loss Expert Panel classification.