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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)

From: Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals

    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
  1. Reference sequences: HNF1A, NM_000545; HNF4A, NM_000457; ABCC8, NM_000352; INS, NM_001185098
  2. aPolyPhen predictions are probably damaging (Pr.D), possibly damaging (Pos.D) and benign
  3. bSIFT predictions are deleterious (del) and tolerated (tol)
  4. cMutationTaster predictions are disease causing (del) and polymorphism (poly)
  5. 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
  6. eInformation about previously observed MODY mutations in the HNF1A and HNF4A genes was obtained from Colclough et al. [79]
  7. fExAC allele frequency is the maximum allele frequency of the variant allele among the different populations reported in the database
  8. gACMG classification: 5 = pathogenic, 4 = likely pathogenic, and 3 = uncertain significance
  9. 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