Low-density lipoprotein receptor (LDLR) missense variants with discordant in silico and in vitro functional studies
| DNA | Peptide | Refined SIFT | SIFT | PolyPhen 2 HumDiv | PolyPhen 2 HumVar | Mutation taster | Structural conservation | In silico prediction (ACGS classification) | In vitro classification (ACGS classification) | In vitro evidence (LDLR defect classification)25 |
|---|---|---|---|---|---|---|---|---|---|---|
| c.226G>T | p.(Gly76Trp) | Not tolerated | Not tolerated | Probably damaging, 1 | Probably damaging, 1 | Disease causing | 0.922 | Likely to be pathogenic4 | Probably not pathogenic2 | Normal LDLR expression, LDL-binding and internalisation26 |
| c.344G>A | p.(Arg115His) | Not tolerated | Tolerated | Benign, 0.157 | Benign, 0.128 | Disease causing | 0.54 | VUS3 | Likely to be pathogenic4 | Retained in ER, 36% reduced LDLR on cell surface, 36% reduced LDL binding and internalisation (class 2)27 |
| c.768C>G | p.(Asp256Glu) | Not tolerated | Not tolerated | Benign, 0.388 | Benign, 0.329 | Disease causing | 0.721 | VUS3 | Likely to be pathogenic4 | 50–70% reduced LDL binding and internalisation, co-segregated with FH in large family (class 3)28 |
| c.769C>T | p.(Arg257Trp) | Not tolerated | Not tolerated | Probably damaging, 0.993 | Probably damaging, 0.916 | Polymorphism | 0.568 | Likely to be pathogenic4 | Probably not pathogenic2 | Normal LDLR expression, LDL-binding and internalisation29 |
| c.895G>A | p.(Ala299Thr) | Tolerated | Tolerated | Benign, 0.192 | Benign, 0.068 | Polymorphism | 0.28 | Probably not pathogenic2 | Likely to be pathogenic4 | 50% reduced LDL binding and internalisation (class 3)30 |
| c.1285G>C | p.(Val429Leu) | Tolerated | Tolerated | Benign, 0.307 | Benign, 0.225 | Disease causing | 0.672 | Probably not pathogenic2 | Likely to be pathogenic4 | Retained in ER, 75% reduced LDLR on cell surface, >80% reduced LDL binding and internalisation (class 2)31 |
| c.1361C>A | p.(Thr454Asn) | Tolerated | Not tolerated | Possibly damaging, 0.475 | Possibly damaging, 0.738 | Polymorphism | 0.711 | VUS3 | Likely to be pathogenic4 | Normal LDLR expression, 40% reduced LDLR on cell surface, 36%, reduced LDL binding and internalisation. Recycling defect (class 5)32 |
| c.1942T>C | p.(Ser648Pro) | Tolerated | Tolerated | Benign, 0.12 | Benign, 0.083 | Polymorphism | 0.537 | Probably not pathogenic2 | Likely to be pathogenic4 | Retained in ER, 80% reduced LDLR on cell surface, 75% reduced LDL binding and internalisation (class 2)31 |
| c.2389G>A | p.(Val797Met) | Not tolerated | Tolerated | Benign, 0.448 | Benign, 0.085 | Disease causing | 0.545 | Probably not pathogenic2 | Likely to be pathogenic4 | RT-PCR disruption of normal gene splicing33 |
| c.2389G>T | p.(Val797Met) | Tolerated | Tolerated | Benign, 0.002 | Benign, 0.007 | Disease causing | 0.545 | Probably not pathogenic2 | Likely to be pathogenic4 | RT-PCR disruption of normal gene splicing, exon skipping34 |
ACGS, Association for Clinical Genetic Science; FH, familial hypercholesterolaemia; LDL, low-density lipoprotein; SIFT, Sorting Intolerant From Tolerant; VUS, variants of unknown significance.