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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)