Table 3.
ACVRL1 genetic variants in HHT patients and their family members (12 families)
| Family No. | Variant location | Variant type | Nucleotide changea) | Protein changea) | Classificationb) | Reference |
|---|---|---|---|---|---|---|
| 5 | Exon 3 | Duplication/frameshift | c.252dup | p.Val85Argfs*84 | Pathogenic (PVS1, PM2, PP1, PP4, PP5) | [10] |
| 6 | Exon 3 | Substitution/missense | c.199C>T | p.Arg67Trp | Likely pathogenic (PM2c), PP1, PP3, PP4, PP5) | [10] |
| 10 | Exon 7 | Substitution/missense | c.925G>A | p.Gly309Ser | Likely pathogenic (PM2, PP1, PP3, PP4, PP5) | [10] |
| 12 | Exon 7 | Substitution/missense | c.781G>C | p.Ala261Pro | Uncertain significance (PM2, PP3, PM4) | This study |
| 16 | Exon 10 | Substitution/nonsense | c.1435C>T | p.Arg479* | Pathogenic (PVS1, PM2, PP1, PP4, PP5) | [10] |
| 17 | Exon 8 | Deletion/frameshift | c.1118del | p.Lys373Serfs*42 | Pathogenic (PVS1, PM2, PP1, PP4, PP5) | [10] |
| 28 | Exon 3 | Duplication/frameshift | c.121dup | p.Cys41Leufs*128 | Pathogenic (PVS1, PM2, PP4) | This study |
| 30 | Exon 5 | Substitution/missense | c.605T>G | p.Val202Gly | Uncertain significance (PM2, PP3, PP4) | This study |
| 32 | Exon 8 | Substitution/missense | c.1124A>G | p.Tyr375Cys | Uncertain significance (PM2, PP3, PP4) | [10] |
| 35 | Exon 9 | Deletion/frameshift | c.1311_1315del | p.Asp437Glufs*15 | Pathogenic (PVS1, PM2, PP4) | This study |
| 38 | Exon 7 | Substitution/missense | c.1005T>G | p.Asn335Lys | Uncertain significance (PM2, PP3, PP4) | This study |
| 40 | Intron 7 | Substitution/splicing defect | c.1048+5G>A | p.? | Likely pathogenic (PS3, PM2, PP4) | [9,20] |
HHT, hereditary hemorrhagic telangiectasia; *, termination by nonsense mutation; PVS, pathogenic very strong; PM, pathogenic moderate; PP, pathogenic supporting; p.?, an effect on the protein level is expected, but it is not possible to give a reliable prediction of the consequences; PS, pathogenic strong.
The reference sequences to describe variants are NC_000012.12 (genomic DNA), NM_000020.3 (coding DNA), and NP_000011.2 (protein).
The classification was based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [17].
One c.199C>T variant indicated as pathogenic is reported in the genome aggregation database.