Table 2.
DUET score for all SDHB and SDHD missense mutations described in this cohort and for rare missense variants with no or unknown pathogenicity
| Mutation | Allele frequency | mCSM stability (Kcal/mol) | DUET (Kcal/mol) | Predicted effect |
| SDHB | – | – | – | – |
| p.Lys40Glu | Unknown | −1.741 | −1.774 | Destabilises protomer and complex |
| p.Arg46Gln | 0.000008238 | −0.997 | −1.02 | Destabilises protomer |
| p.Gly96Ser | 0.000008381 | −1.024 | −1.09 | Destabilises protomer; positive phi glycine; affect metal binding |
| p.Cys98Arg | Unknown | 0.217 | 0.316 | Affect metal binding; destabilse complex |
| p.Gly99Asp | Unknown | −0.989 | −1.216 | Destabilises protomer and complex; affect metal binding |
| p.Ser100Pro | Unknown | −0.226 | −0.368 | Affect metal binding; destabilse complex |
| p.Cys101Tyr | Unknown | −1.06 | −1.651 | Destabilises protomer; affect metal binding |
| p.Cys113Tyr | Unknown | −0.974 | −1.467 | Destabilises protomer and complex; affect metal binding |
| p.Ile127Asn | Unknown | −3.088 | −3.213 | Destabilises protomer. Mildly destabilises complex |
| p.Ile127Ser | Unknown | −3.669 | −3.856 | Destabilises protomer |
| p.Val140Phe | Unknown | −1.233 | −1.353 | Destabilises protomer. Mildly destabilises complex |
| p.Cys196Tyr | Unknown | −1.407 | −1.77 | Destabilises protomer and complex; affect metal binding |
| p.Pro197Arg | Unknown | −0.954 | −0.784 | Destabilises protomer; mildly destabilises complex; affect metal binding; loss of conformational restraint |
| p.Trp200Cys | Unknown | −1.442 | −1.205 | Destabilises protomer and complex |
| p.Arg217Cys | Unknown | −1.916 | −1.948 | Destabilises protomer and complex |
| p.Arg217Leu | Unknown | −1.031 | −0.879 | Destabilises protomer and complex |
| p.Arg230Gly | Unknown | −1.848 | −2.45 | Destabilises protomer and complex |
| p.Arg230Cys | 0.000008252 | −1.739 | −1.836 | Destabilises protomer and complex |
| p.Arg230His | Unknown | −1.903 | −2.133 | Destabilises protomer |
| p.Arg242Cys | Unknown | −1.386 | −1.619 | Destabilises protomer; mildly destabilises complex; affect metal binding |
| p.Arg242His | 0.00002471 | −1.948 | −2.035 | Destabilises protomer; mildly destabilises complex; affect metal binding |
| SDHD | – | – | – | – |
| p.Pro81Leu | Unknown | −0.297 | 0.036 | Destabilising transmembrane |
| p.Asp92Tyr | Unknown | −0.907 | −0.868 | Destabilising transmembrane |
| p.Tyr114Cys | Unknown | 0.236 | 0.388 | Stabilising |
| Mutations with no or unknown pathogenicity | ||||
| Mutation | Allele frequency | mCSM | DUET | Predicted effect |
| SDHB | – | – | – | – |
| p.Ala3Gly | 0.00436 | −0.28 | −0.244 | Neutral |
| p.Thr17Ala | Unknown | −0.943 | −0.82 | Destabilising |
| p.Cys22Ser | 0.0001331 | 0.119 | 0.135 | Neutral |
| p.Arg27Gly | 0.00004183 | −0.229 | −0.208 | Neutral |
| p.His57Arg | 0.0007249 | −0.238 | 0.011 | Neutral |
| p.Ser100Phe | Unknown | −0.226 | −0.368 | Neutral |
| p.Ser163Pro | 0.01254 | −0.136 | −0.03 | Introduction of a conformational restraint |
| SDHD | – | – | – | – |
| p.Gly12Ser | 0.007268 | −0.377 | −0.134 | Altered localisation |
| p.Arg17Leu | Unknown | 0.549 | 0.481 | Mildly stabilising |
| p.Ile40Val | 0.00003295 | −0.461 | −0.182 | Neutral |
| p.Glu42Ala | Unknown | −0.255 | −0.017 | Neutral |
| p.His50Arg | 0.006515 | −0.4 | −0.155 | Altered localisation |
| p.Pro87His | Unknown | −0.571 | −0.442 | Neutral |
| p.His145Asn | Unknown | −0.055 | 0.018 | Neutral |
Allele frequencies are as reported in the ExAC database (Exome Aggregation Consortium, Cambridge, Massachusetts, USA), all ethnicities, accessed 17 June 201761