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. Author manuscript; available in PMC: 2015 Jun 8.
Published in final edited form as: Ophthalmology. 2014 Oct 12;122(2):326–334. doi: 10.1016/j.ophtha.2014.08.012

Table 4. Suggested Pathogenicity of the 46 ABCA4 Variants Identified in Childhood-onset Stargardt Disease.

Exon/
IVS		 Nucleotide
substitution		 Protein
change/effect		 Number of alleles
identified		 Pt Reference SIFT Polyphen2 HSF Allelic
frequency
observed
by EVS		 db SNP
Prediction Prediction Hum var
score (0-1)		 Wild type
CV		 Mutant
CV		 effect
1 c.21dupA p.Gln8fs 1 20 This study ND
6 c.634C>T p.Arg212Cys 1 7 Simonelli F et al.30 Not tolerated PRD 0.951 0.0116 rs61750200
6 c.768G>T Splice 1 17 Klevering et al.28 91.6 80.7 weakens the splice donor site by ∼12% ND
10 c.1317G>A p.Trp439* 1 21 Fujinami et al.5 ND
11 c.1531C>T p.Arg511Cys 1 37 Zernant et al.22 Not tolerated PRD 0.976 ND
12 c.1557C>A p.Cys519* 1 12 This study ND
12 c.1648G>A p.Gly550Arg 1 26 Shroyer et al.27 Not tolerated POD 0.882 0 81.58 creates a new splice acceptor site ND
12 c.1757A>G p.Asp586Gly 1 39 This study Not tolerated POD 0.599 ND
12 c.1760G>A p.Arg587Lys 1 29 This study Not tolerated POD 0.749 84.6 74 weakens the splice donor site by ∼13% ND
13 c.1906C>T p.Gln636* 3 2, 18, 30 Zernant et al.22 0.0116 rs145961131
14 c.1957C>T p.Arg653Cys 1 36 Rivera et al.25 Not tolerated PRD 0.999 ND
16 c.2564G>A p.Trp855* 1 29 Rivera et al.25 rs61752406
17 c.2588G>C p.Gly863Ala/ p.Gly863del 2 25, 27 Lewis et al.24/Maugeri et al.34 Not tolerated POD 0.864 0.6744 rs76157638
18 c.2712delG p.Glu905fs 2 5 This study ND
19 c.2861A>C p.Tyr954Ser 1 16 Aguirre-Lamban et al.32 Not tolerated PRD 0.959 ND
21 c.3056C>T p.Thr1019Met 1 31 Rozet et al.23 Not tolerated PRD 1.000 ND rs201855602
21 c.3064G>A p.Glu1022Lys 2 28 Webster et al.26 Not tolerated PRD 1.000 ND rs61749459
21 c.3081T>G p.Tyr1027* 2 8 This study ND
22 c.3197T>G p.Met1066Arg 1 38 This study Not tolerated POD 0.495 ND
22 c.3259G>A p.Glu1087Lys 1 10 Lewis et al. 1999 Not tolerated PRD 0.997 ND rs61751398
22 c.3289A>T p.Arg1097* 1 6 This study ND
22 c.3322C>T p.Arg1108Cys 2 11, 13 Rozet et al.23 Not tolerated PRD 0.986 0.0116 rs61750120
23 c.3364G>A p.Glu1122Lys 1 25 Lewis et al.24 Not tolerated PRD 1.000 ND rs61751399
23 c.3385C>T p.Arg1129Cys 1 42 Zernant et al.22 Not tolerated PRD 0.998 ND
28 c.4139C>T p.Pro1380Leu 3 21, 34, 36 Lewis et al.24 Not tolerated PRD 0.99 0.0233 rs61750130
28 c.4216C>T p.His1406Tyr 1 14 Lewis et al.24 Not tolerated POD 0.824 ND rs61750133
28 c.4222T>C p.Trp1408Arg 1 14 Lewis et al.24 Not tolerated PRD 0.973 ND rs61750135
30 c.4363T>C p.Cys1455Arg 2 17, 24 Fujinami et al.5 Not tolerated PRD 0.999 ND
30 c.4469G>A p.Cys1490Tyr 4 9, 11, 38, 42 Lewis et al.24 Not tolerated PRD 0.994 ND rs61751402
31 c.4577C>T p.Thr1526Met 1 13 Lewis et al.24 Not tolerated PRD 0.999 ND rs61750152
36 c.4918C>T p.Arg1640Trp 1 14 Briggs et al.22 Not tolerated PRD 0.999 ND
36 c.5160_5161delCA p.Thr1721fs 1 27 This study ND rs61750566
37 c.5308T>G p.Tyr1770Asp 1 34 This study Not tolerated PRD 1.000 ND
37 c.5213_5214insTGC p.Ala1739dup 1 37 This study ND
42 c.5882G>A p.Gly1961Glu 5 31, 33, 35, 37, 39 Lewis et al.24 Not tolerated PRD 1.000 0.4186 rs1800553
44 c.6079C>T p.Leu2027Phe 3 22, 40, 41 Lewis et al.24 Not tolerated PRD 1.000 0.0349 rs61751408
44 c.6088C>T p.Arg2030* 2 2, 25 Lewis et al.24 ND rs61751383
45 c.6215G>A p.Ser2072Asn 1 32 This study Not tolerated PRD 1.000 ND
47 c.6449G>A p.Cys2150Tyr 1 26 Fishman et al.16 Not tolerated PRD 1.000 0.0116 rs61751384
IVS35 c.5018+2T>C splice 1 32 Fujinami et al.8 81.15 0 eliminates the splice donor site ND
IVS36 c.5196+1G>A splice 1 6 Shroyer et al.27 83.28 0 eliminates the splice donor site ND
IVS38 c.5461-10T>C Uncertain 9 7, 9, 10, 15, 16, 18, 20, 22, 41 Briggs et al.20 0.0349 rs1800728
IVS40 c.5714+5G>A splice 1 24 Cremers et al.19 85.49 73.33 weakens the splice donor site by ∼14% 0.1512
IVS47 c.6479+1G>A splice 2 3 Zernant et al.22 87.25 0 eliminates the splice donor site ND
IVS48 c.6729+4_6729+18d elAGTTGGCCCTG GGGC splice 1 33 Littink et al.31 ND
IVS49 c.6817-2A>C splice 1 30 This study 93.6 0 eliminates the splice acceptor site ND

CV = consensus value; EVS = Exon variant server; Het = heterozygous; Hom = homozygous; HSF = human splicing finder; Hum Var Score = human var score; IVS = intervening sequence; NA = not applicable; ND= not detected; POD = possibly damaging; PRD = probably damaging; Pt = patient; SIFT = Sorting Intolerant From Tolerant ; WT = wild type.

SIFT (version 4.0.4) results are reported to be tolerant if tolerance index ≥ 0.05 or intolerant if tolerance index < 0.05. [http://sift.bii.a-star.edu.sg/www/SIFT_BLink_submit.html/. Accessed February 1, 2013.] Polyphen 2 (vision 2.1) appraises mutations qualitatively as Benign, Possibly Damaging or Probably Damaging based on the model's false positive rate. [http://genetics.bwh.harvard.edu/pph2/. Accessed November 1, 2013.] HumanVar-trained model of Polyphen 2 was selected, since diagnostics of mendelian diseases requires distinguishing mutations with drastic effects from all the remaining human variation, including abundant mildly deleterious alleles. The cDNA is numbered according to Ensemble transcript ID ENST00000370225, in which +1 is the A of the translation start codon. Human Splicing Finder (HSF, version 2.4.1) reports the results from the HSF matrix: the higher the consensus value, the stronger the predicted splice site. The values for the wildtype and mutant sequences are shown; the larger the difference between these values, the greater the chance that the variant can affect splicing [http://www.umd.be/HSF/. Accessed November 1, 2013.]. EVS denotes the allele frequencies of variants on the Exome Variant Server, NHLBI Exome Sequencing Project, Seattle, WA, USA. [http://snp.gs.washington.edu/EVS/. Accessed Febrary 1, 2013.]