Table 3.
List of missense mutations in the HNF1A, HNF4A, HNF1B, INS, and ABCC8 genes that have previously been reported in individuals or families with MODY or early onset diabetes. The ABCC8 gene was sequenced in a subset of individuals (2132 cases and 1024 controls)
| Counts | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | cDNA change | AA change | Cases | Early onset | Controls | PolyPhen2a | SIFTb | MutationTasterc | CADDd | Previously observed in MODY/diabetese | ExAC AFf | dbSNP 144 | ACMG classg |
| HNF1A | c.391C > T | p.R131W | 1 | 1 | 0 | Pr.D | del | del | 31 | 29 families | ─ | rs137853244 | 5 |
| HNF1A | c.608G > A | p.R203H | 2 | 1 | 0 | Pos.D | del | del | 29 | 19 individuals | ─ | rs587780357 | 4 |
| HNF1A | c.812G > A | p.R271Q | 1 | 1 | 0 | Pr.D | del | del | 34 | 13 individuals | 0.00007 | rs779184183 | 4 |
| HNF1A | c.779C > T | p.T260M | 1 | 1 | 0 | Pr.D | del | del | 33 | 13 families | ─ | ─ | 4 |
| HNF1A | c.1340C > T | p.P447L | 1 | 1 | 0 | Pr.D | del | del | 34 | 11 studies | ─ | rs137853236 | 5 |
| HNF1A | c.1135C > G | p.P379A | 1 | 1 | 0 | Pr.D | del | del | 25 | 10 studies | 0.0006 | rs754729248 | 4 |
| HNF1A | c.815G > A | p.R272H | 1 | 0 | 0 | Pr.D | del | del | 34 | 20 families | ─ | rs137853238 | 5 |
| HNF1A | c.1061C > T | p.T354M | 2 | 1 | 0 | benign | tol | poly | 23 | 3 individuals | 0.00006 | rs757068809 | 3 |
| HNF1A | c.1513C > A | p.H505N | 1 | 0 | 0 | Pos.D | tol | del | 26.1 | 3 individuals from one study | 0.00017 | rs577078110 | 4 |
| HNF1A | c.1400C > T | p.P467L | 1 | 0 | 0 | benign | del | del | 20.8 | 3 individuals | 0.000015 | ─ | 3 |
| HNF1A | c.481G > A | p.A161T | 0 | 0 | 1 | Pos.D | del | del | 31 | 1 individual | 0.00024 | rs201095611 | 3 |
| HNF1A | c.503G > A | p.R168H | 0 | 0 | 2 | Pos.D | del | del | 32 | 1 individual | 0.00006 | rs377110124 | 3 |
| HNF1A | c.403G > A | p.D135N | 1 | 1 | 0 | Pos.D | del | del | 32 | 1 individual | ─ | ─ | 3 |
| HNF1A | c.1699G > A | p.V567I | 1 | 0 | 0 | benign | tol | poly | 18.8 | 1 individual | 0.0001 | ─ | 3 |
| HNF4A | c.400C > T | p.R134W | 1 | 1 | 0 | Pos.D | del | del | 35 | 5 families | ─ | rs370239205 | 4 |
| HNF4A | c.406C > T | p.R136W | 2 | 0 | 0 | Pos.D | del | del | 34 | 36 families | 0.0001 | rs137853336 | 5 |
| HNF4A | c.929G > A | p.R310Q | 2 | 0 | 0 | Pr.D | tol | del | 24.7 | 1 family/co-segregation with diabetes [80] | 0.00003 | rs371124358 | 4 |
| ABCC8 | c.886G > A | p.G296R | 1 | 1 | 0 | benign | del | del | 27.1 | Individual with diabetes at 7 months [82] | 0.00006 | rs148529020 | 3 |
| ABCC8 | c.1067A > G | p.Y356C | 1 | 0 | 0 | Pr.D | del | del | 26.1 | Early onset diabetes family [78] | 0.00005 | rs59852838 | 4 |
| ABCC8 | c.2473C > T | p.R825W | 2 | 1 | 0 | Pr.D | del | del | 35 | Multiple individuals with NDM [83] | 0.00001 | rs779736828 | 4 |
| ABCC8 | c.4136G > A | p.R1379H | 1 | 1 | 0 | Pr.D | del | del | 34 | One individual with transient NDM [81] | ─ | ─ | 3 |
| ABCC8 | c.4516G > A | p.E1506K | 1 | 1 | 0 | Pr.D | del | del | 35 | Finnish family [77] | ─ | rs137852671 | 5 |
| INS | c.16C > T | p.R6C | 1 | 0 | 0 | ─ | del | del | 22.7 | Three-generation MODY family [76] | 0.00006 | rs121908278 | 5 |
Reference sequences: HNF1A, NM_000545; HNF4A, NM_000457; ABCC8, NM_000352; INS, NM_001185098
aPolyPhen predictions are probably damaging (Pr.D), possibly damaging (Pos.D) and benign
bSIFT predictions are deleterious (del) and tolerated (tol)
cMutationTaster predictions are disease causing (del) and polymorphism (poly)
dCADD scaled C-scores range from 0-30. Higher CADD scores correspond to more deleterious variants; a CADD score of 20 (30) corresponds to the top 1% (0.1%) of deleterious substitutions in the human genome
eInformation about previously observed MODY mutations in the HNF1A and HNF4A genes was obtained from Colclough et al. [79]
fExAC allele frequency is the maximum allele frequency of the variant allele among the different populations reported in the database
gACMG classification: 5 = pathogenic, 4 = likely pathogenic, and 3 = uncertain significance
AA amino acid, ACMG American College of Medical Genetics, AF allele frequency, dbSNP Single Nucleotide Polymorphism Database, ExAC Exome Aggregation Consortium, NA not available, NDM neonatal diabetes mellitus