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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