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Table 2 Computational biology characterization of detected variants

From: Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

Proband IDa

Mean BDSIb [%]

Variant

Location of variant residue in human BEST1 3D structure

Possible structural consequences of residue replacement

Relative energy of dimerization ΔΔE cdim [kcal mol−1]

Relative energy of Ca2+ binding ΔΔE dCabin [kcal mol−1]

PMVA predicted pathogenicity of BEST1 variant in logMAR scalee

P1

11.90

p.(Thr2Ile)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 23

− 91

0.24

P2, P3

3.55

p.(Thr4Ile)

At interface to subunits B and E of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 13

9

0.19

P4

17.60

p.(Val9Gly)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 34

62

0.29

P5–P7

7.10

p.(Gly15Asp)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 1

4

0.13

P8

17.60

p.(Ser16Phe)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and/or pore shape

Channel stability

Channel activation

50

− 19

0.37

P9

15.30

p.(Arg25Gln)

At interface of cacc to cell membrane

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel embedding in cell membrane

Channel pore shape and stability

Channel activation

11

− 49

0.18

P10–P12

23.10

p.(Ser27Thr)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 71

16

0.47

P13

0.00

p.(Tyr29Cys)

At interface to subunit B of cacc

Close to K+ binding site of subunit B

Close to Ca2+ binding site of subunit B

Channel formation and stability

Channel pore shape

Channel activation

− 13

− 3

0.19

P14

NA

p.(Arg92Cys)

Lining pore wall of cacc

Close to Ca2+ binding site of subunit A

At interface to subunit E of cacc

Conformational changes, channel gating

Chloride ion throughput or ion selectivity

Channel activation

Channel stability

12

− 23

0.19

P15

NA

p.(Trp93Ser)

Close to pore wall of cacc

Close to Ca2+ binding site of subunit A

At interface to subunit B of cacc

Conformational changes, channel gating

Chloride ion throughput or ion selectivity

Channel activation

Channel stability

12

− 15

0.19

P16

9.50

p.(Pro101Thr)

Lining pore wall of cacc

Near interface to subunit B of cacc

Conformational changes, channel gating

Chloride ion throughput or ion selectivity

Channel stability

− 17

− 24

0.21

P17

32,60

p.(Ser108Arg)

At interface to subunit B of cacc

Channel formation and/or pore shape

Channel stability

96

− 7

0.59

P18

15.30

p.(Asn179Asp)

At interface to subunits D and E of cacc

Channel formation and/or pore shape

Channel stability

23

− 50

0.24

P19

NA

p.(Trp182Arg)

At interface to subunit E of cacc

Channel formation and/or pore shape

Channel stability

26

25

0.25

P20

NA

p.(Arg200*)

Cytoplasm side of cacc

Channel gating

P21–P23

7.60

p.(Arg218Cys)

At interface to subunit E of cacc

Near Cl binding site

Channel stability

Channel formation and/or pore shape

− 1

25

0.13

P24

23.40

p.(Arg218Ser)

At interface to subunit E of cacc

Near Cl binding site

Channel stability

Channel formation and/or pore shape

32

55

0.28

P25

31.40

p.(Ile232Asn)

At interface to subunit E of cacc

Near pore wall of cacc

Close to Ca2+ binding site of subunit A

Channel stability

Conformational changes, channel gating

Chloride ion throughput or ion selectivity

Channel activation

21

− 46

0.23

P26

6.50

p.(Val235Leu)

At interface to subunit E of cacc

Channel formation and stability

6

7

0.16

P27

46.20

p.(Ala243Thr)

At interface to subunit E of cacc

Channel formation and stability

5

− 47

0.15

P28–P30

6.50

p.(Ala243Val)

At interface to subunit E of cacc

Channel formation and stability

− 7

− 48

0.16

P31

70.30

p.(Glu292Gln)

At Ca2+ binding site of subunit A

Close to K+ binding site of subunit A

At interface to subunit E of cacc

Channel activation

Channel stability

Channel formation and stability

− 14

42

0.20

P32, P33

12,85

p.(Asn296Lys)

At Ca2+ binding site of subunit A

At interface to subunit E of cacc

Channel activation

Channel formation and stability

− 17

80

0.21

P34, P35

NA

p.(Phe298Cys)

Near Ca2+ binding site of subunit A

Near interface to subunit E of cacc

Channel activation

Channel formation and stability

26

− 35

0.25

P36

18.70

p.(Asp301Glu)

At Ca2+ binding site of subunit A

At interface to subunit E of cacc

At interface of cacc to cell membrane

Channel activation

Channel formation and stability

Channel embedding in cell membrane

− 60

− 7

0.42

  1. aProbands bearing the same amino acid replacement are grouped together
  2. bMean age-adjusted Best’s Disease Severity Index (%BDSI) of probands bearing the same bestrophin-1 variant as defined in Eq. (5). In our cohort the number of probands sharing the same variant ranges from 1 to 3. On the logMAR scale, logMARLE,i + logMARRE,I = 0 for a person with standard vision and 2.6 for a completely blind proband. Examples of BDSI index: BDSI(logMARLE, logMARLE, Age) = BDSI (0, 0, 100) = 0% means no Best’s disease symptoms during whole lifetime (100 years); BDSI(1.3, 1.3, 1) = 100% means the most severe Best’s disease symptoms—complete (100%) loss of vision from early childhood; BDSI (0.4, 0.6, 40) = 26% means relatively mild Best’s disease symptoms (26% loss of vision) at age 40 years
  3. cRelative energy of human BEST1 dimerization ΔΔEdim estimates the extent of damage to CaCC as the change in binding energy between two neighbouring bestrophin-1 subunits A and B in CaCC caused by a variant, as compared to the reference native protein BEST1, see Eqs. (1) and (2), Methods
  4. dRelative Ca2+ binding energy ΔΔECabin estimates quantitative damage to channel regulation expressed as altered ability of BEST1 dimer AB to bind calcium ions caused by a variant, compared to the reference native protein BEST1, see Eqs. (3) and (4) Methods
  5. ePathogenicity of a given BEST1 variant: PMVA—Predicted Mean Visual Acuity (logMARLE + logMARRE)/2 of an individual with a given bestrophin-1 variant at age 40 years in the logMAR scale. The PMVA calculated from Eq. (7) is based on the modulus of computed relative energy of variant BEST1 subunit dimerization |ΔΔEdim| with respect to native human BEST1 and regression equation of the QSAR model of BEST1 dimerization: BDSI = 0.24935·|ΔΔEdim| + 6.56527 (Fig. 7)