Table 2.
Low-density lipoprotein receptor intronic variants affecting residues >±1 or 2
| Intron | Variant | Pathogenicity classification | In vitro evidence | Mechanism |
|---|---|---|---|---|
| 2 | c.190+2_190+3dup | Clearly pathogenic5 | cDNA sequencing revealed use of novel splice donor site (GT) at c.190+3_190+4, resulting in inclusion 2 bp from 5′ end of intron 2, a frame shift and premature truncation of the peptide—p.(Leu64Cysfs*143).35 | Use of novel splice site |
| 3 | c.313+2dup | Likely to be pathogenic4 | RT-PCR sequencing revealed skipping of exon 3, resulting in an in-frame deletion—p.(Leu64_Pro105delinsSer).30 | Inactivation of wild-type splice site |
| 3 | c.313+5G>A | Likely to be pathogenic4 | cDNA sequencing revealed skipping of exon 3, resulting in an in-frame deletion—p.(Leu64_Pro105delinsSer).36 | Inactivation of wild-type splice site |
| 3 | c.313+6T>C | Likely to be pathogenic4 | cDNA sequencing revealed skipping of exon 3, resulting in an in-frame deletion—p.(Leu64_Pro105delinsSer).34 | Inactivation of wild-type splice site |
| 6 | c.941-12G>A | Likely to be pathogenic4 | RT-PCR sequencing revealed abnormal splicing of intron 6 (no further information provided by authors).37 | Unknown |
| 7 | c.1061-8T>C | Clearly not pathogenic1 | RT-PCR sequencing reveals normal splicing of intron 7.34 | Normal splicing |
| 8 | c.1186+5G>A | Clearly pathogenic5 | RT-PCR sequencing revealed inclusion of intron 8, resulting in a frame shift and premature truncation of the peptide—p.(Gly396fs*26).30 | Use of novel splice site |
| 8 | c.1187-10G>A | Clearly pathogenic5 | cDNA sequencing reveals creation of novel acceptor site resulting in inclusion of 8 bp (ACCCCCAG) from 3′ end of intron 8, a frame shift and premature truncation of the peptide—p.(Gly396Aspfs*20).38 | Use of novel splice site |
| 9 | c.1359-31_1359-23delinsCGGCT | Clearly pathogenic5 | mRNA sequencing revealed retention of intron 9 and evidence that two additional transcripts are produced using cryptic splice sites in exon 10. Due to removal of the invariant A at consensus splicing branch site in intron 9.39 | Use of novel splice sites |
| 9 | c.1359-5C>G | Clearly pathogenic5 | mRNA sequencing revealed retention of intron 9, resulting in a frame shift and premature truncation of the peptide—p.(Ser453Argfs*1).34 | Inactivation of wild-type splice site |
| 10 | c.1586+5G>A | Likely to be pathogenic4 | RT-PCR sequencing revealed alternate splicing resulting in two abnormal mRNAs: (a) skipping of exon 10 and (b) inclusion of 22 novel amino acids from the activation of a cryptic splice site.40 | Inactivation of wild-type splice site and use of cryptic splice site |
| 12 | c.1845+11C>G | Likely to be pathogenic4 | RT-PCR revealed that approximately half the transcripts use the novel splice site, resulting in inclusion of 11 bp from 5′ end of intron 12 into the transcript, a frame shift and premature truncation of the peptide—p.(Glu615fs*53).41 | Normal splicing and use of novel splice site |
| 14 | c.2140+5G>A | Unlikely to be pathogenic2 | RT-PCR sequencing reveals normal splicing of intron 14.34 | Normal splicing |
| 14 | c.2140+86C>G | Likely to be pathogenic4 | RT-PCR sequencing revealed creation of a novel splice donor site, resulting in inclusion of 81 bp from 5′ end of intron 14 and a 27aa insertion into peptide p.(Thr713_Glu714ins27). Resulting peptide fails to leave the ER.42 | Use of novel splice site |
| 15 | c.2312-3C>A | Likely to be pathogenic4 | cDNA sequencing reveals skipping of exon 16, predicted to result in an in-frame deletion—p.(Ala771_Ile796del).36 | Inactivation of wild-type splice site |