Table 2 In silico predicted residual activity of CYP21A2 stability mutants lacking functional assays.

From: Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations

Variant

Patient’s second mutation (% REA)

Patient’s phenotype

Expected activity of the variant

∆∆G

In silico activity (%)

Reference

p.H38L

NA

NA

?

−1.64

100

26

p.Y47C

NA

NA

?

−1.64

100

27

p.Y59N

NA

CL

0–5

2.54

4.4

28

p.V69L

p.[Q318;.R356] (0) pH62L in cis*

SV

5–60

1.47

22.5

29

p.S113Y

p.V281L (60)

NC

0–60

0.79

63.3

30

p.S113F

NA

NA

?

1.05

42.6

20

p.Q144P

p.P482fs (ND)

SW

0

0.61

83.2

29

p.F164S

p.I172N (2)

SV

0–5

1.37

26.2

29

p.S165P

p.I172N (2)

NC

10–60

4.94

0.1

31

p.T168N

Chimeric gene (0)

NC

10–60

3.41

1.2

32

p.V211L

NA

N?

?

−0.91

100

33

p.E238K

NA

4 SW, 1 NC

0#

−0.33

100

34

p.V249A

NA

N

100

0.45

100

35

p.L261P

c.290-13A/C>G** (0–2)

SW

0

8.95

0.01

36

p.M283L

p.V281L (60)

NC

0–60

−0.3

100

37

p.S301Y

c.290-13A/C>G** (0–2)

NC

10–60

12.31

0.00

38

p.V304E

c.290-13A/C>G** (0–2)

SW

0

2.44

5.1

29

p.V305D

NA

NA

?

0.99

46.6

20

p.F306V

NA

NA

?

1.87

12.2

20

p.L307V

Deletion (0)

NC

10–60

2.8

2.9

30

p.R316L

p.V281L (60)

NC

0–60

0.03

100

30

p.L317M

c.290-13A/C>G** (0–2)

NC

10–60

−0.8

100

39

p.L317V

N

NC§

?

2.42

5.3

40

p.L321P

NA

NA

?

9.84

0.0

20

p.G381S

NA

NA

?

3.51

1.0

20

p.N387K

p. V281L (60)

NC

0–60

7.55

0.0

41

p.F404S

p.F404S (ND)

SW

0

5.34

0.06

42

p.F404L

p.V281L (60)

NC

0–60

2.51

4.6

30

p.T450P

p.T450P (ND)

SW

0

9.35

0.0

42

p.P459H

p.[ClEx6; Q318X; A391T] (0)

SV

2–5

4.44

0.2

43

p.P459S

Chimeric Gene

SV

2–5

2.68

3.6

32

p.P459L

c.290-13A/C>G** (0–2)

SV

0–5

1.29

29.5

29

  1. In silico predicted activities of mutants lacking functional assays were compared with the expected ones. Expected activity was established considering the residual activity of the mutation on the homologous allele and/or the patient’s phenotype when available. In silico enzymatic activities were calculated from the fitting based on the bovine template using the estimated ∆∆G of each of the variants (Table S1). Activities are expressed relative of the wild type protein (100%). *According to functional assays, p.H62L mutation was classified as a mild mutation. Nevertheless, several alleles were described having another mild mutation in cis with decreased enzymatic activities most likely related to the SV form of the disease50,60. **c.290-13A/C>G mutation creates a new acceptor splice site. Patients bearing this mutation have been described presenting either a SW or a SV phenotype8. #The classification of the expected activity for this variant was based on the fact that 4/5 patients presented a SW phenotype. §The patient described by Byounga et al.40, disclosed a 17-OHP post ACTH value of 6, 67 ng/mL. According to the current inclusion criteria, patients would be classified as presenting a NC form of the disease when the post ACTH test is at least 10 ng/mL61. REA: Residual enzymatic activity. NA: Not available, ND: Not determined; N. Normal; NC. Nonclassical; SV: Simple virilizing; SW: Salt wasting; CL: Classical; N: Normal; ClEx6: Cluster Exon 6 mutations. ?: Insufficient data to estimate the expected enzymatic activity.
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