ABCA4 p.Thr1117Ile
| Predicted by SNAP2: | A: N (57%), C: N (53%), D: D (53%), E: N (57%), F: D (66%), G: D (59%), H: N (61%), I: D (53%), K: N (66%), L: D (59%), M: N (53%), N: N (66%), P: D (59%), Q: N (53%), R: N (53%), S: N (72%), V: N (57%), W: D (80%), Y: D (63%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, V: D, W: D, Y: D, |
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[hide] Analysis of the ABCA4 gene by next-generation sequ... Invest Ophthalmol Vis Sci. 2011 Oct 31;52(11):8479-87. doi: 10.1167/iovs.11-8182. Zernant J, Schubert C, Im KM, Burke T, Brown CM, Fishman GA, Tsang SH, Gouras P, Dean M, Allikmets R
Analysis of the ABCA4 gene by next-generation sequencing.
Invest Ophthalmol Vis Sci. 2011 Oct 31;52(11):8479-87. doi: 10.1167/iovs.11-8182., [PMID:21911583]
Abstract [show]
PURPOSE: To find all possible disease-associated variants in coding sequences of the ABCA4 gene in a large cohort of patients diagnosed with ABCA4-associated diseases. METHODS: One hundred sixty-eight patients who had been clinically diagnosed with Stargardt disease, cone-rod dystrophy, and other ABCA4-associated phenotypes were prescreened for mutations in ABCA4 with the ABCA4 microarray, resulting in finding 1 of 2 expected mutations in 111 patients and 0 of 2 mutations in 57 patients. The next-generation sequencing (NGS) strategy was applied to these patients to sequence the entire coding region and the splice sites of the ABCA4 gene. Identified new variants were confirmed or rejected by Sanger sequencing and analyzed for possible pathogenicity by in silico programs and, where possible, by segregation analyses. RESULTS: Sequencing was successful in 159 of 168 patients and identified the second disease-associated allele in 49 of 103 (~48%) of patients with one previously identified mutation. Among those with no mutations, both disease-associated alleles were detected in 4 of 56 patients, and one mutation was detected in 10 of 56 patients. The authors detected a total of 57 previously unknown, possibly pathogenic, variants: 29 missense, 4 nonsense, 9 small deletions and 15 splice-site-altering variants. Of these, 55 variants were deemed pathogenic by a combination of predictive methods and segregation analyses. CONCLUSIONS: Many mutations in the coding sequences of the ABCA4 gene are still unknown, and many possibly reside in noncoding regions of the ABCA4 locus. Although the ABCA4 array remains a good first-pass screening option, the NGS platform is a time- and cost-efficient tool for screening large cohorts.
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No. Sentence Comment
120 Novel Variants Detected by NGS in the ABCA4 Gene and Results of Analysis Using Bioinformatics Software Nucleotide Change Protein Splicing Score Original Splicing Score for New Variant Average Difference Polyphen SIFT SpliceSite Finder-like Gene Splicer SpliceSite Finder-like Gene Splicer c.91Tb0e;C p.W31R 0 0 0 0 0 Probably damaging (0.999) W c.184Cb0e;T p.P62S 0 0 0 0 0 Probably damaging (0.999) P c.770Tb0e;G p.L257R 0 0 0 0 0 Possibly damaging (0.308) m i F L c.1253Tb0e;C p.F418S 0 0 0 0 0 Probably damaging (0.999) F c.1531Cb0e;T p.R511C 0 0 0 0 0 Probably damaging (1.000) R c.1745Ab0e;G p.N582S 0 0 0.74 0.82 77.8 Probably damaging (0.894) d K N c.1868Ab0e;G p.Q623R 0 0.24 0 0 12.1 Probably damaging (0.937) Q c.1964Tb0e;G p.F655C 0 0 0 0 0 Probably damaging (0.999) F c.1977Gb0e;A p.M659I 0 0 0.75 0.85 79.8 Probably damaging (0.999) M c.2243Gb0e;A p.C748Y 0 0 0 0 0 Probably damaging (0.928) g S A C c.2401Gb0e;A p.A801T 0 0 0 0 0 Probably damaging (0.98) A c.2893Ab0e;T p.N965Y 0 0 0 0 0 Probably damaging (0.999) N c.3148Gb0e;A p.G1050S 0 0 0 0 0 Possibly damaging (0.786) G c.3205Ab0e;G p.K1069E 0 0 0 0 0 Probably damaging (0.993) K c.3279Cb0e;A p.D1093E 0 0 0 0 0 Probably damaging (0.99) D c.3350Cb0e;T p.T1117I 0 0 0 0 0 Probably damaging (0.995) T c.3655Gb0e;C p.A1219P 0.77 0 0.74 0 1.5 Probably damaging (0.991) A c.3812Ab0e;G p.E1271G 0.8 0.35 0.71 0 21.8 Probably damaging (0.995) E c.4177Gb0e;A p.V1393I 0 0 0 0 0 Benign (0.000) VI c.4217Ab0e;G p.H1406R 0 0 0 0 0 Probably damaging (0.986) r p q a t k e g n S D H c.4248Cb0e;A p.F1416L 0.79 0.1 0.79 0.1 0.27 Probably damaging (0.891) F c.4326Cb0e;A p.N1442K 0 0 0 0 0 Possibly damaging (0.374) a g d s T N c.4467Gb0e;T p.R1489S 0.85 0.43 0.78 0.24 12.8 Benign (0.047) p h l s n a e T Q K R c.4670Ab0e;G p.Y1557C 0.85 0.13 0.80 0 8.8 Probably damaging (0.999) f W Y c.5138Ab0e;G p.Q1713R 0 0 0 0 0 Probably damaging (0.997) Q c.5177Cb0e;A p.T1726N 0 0 0 0 0 Probably damaging (0.880) s A T c.5646Gb0e;A p.M1882I 0 0 0.75 0 37.4 Probably damaging (0.999) M c.6306Cb0e;A p.D2102E 0 0 0 0 0 Probably damaging (0.99) D c.6718Ab0e;G p.T2240A 0 0 0 0 0 Probably damaging (0.991) T c.160af9;2Tb0e;C 0.81 0.86 0.79 0 44.4 c.1240afa;2Ab0e;G 0.82 0.81 0 0 81.5 c.2382af9;1Gb0e;A 0.79 0.64 0 0 71.7 c.2919afa;2Ab0e;G 0.9 0.92 0 0 90.9 c.3522af9;5delG 0.87 0.57 0 0.18 63 c.3523afa;1Gb0e;A 0.9 0.89 0 0 89 Splice site shift of 1 bp c.3814afa;2Ab0e;G 0.91 0.9 0 0 90.6 c.4352af9;1Gb0e;A 0.74 0.82 0 0 78 c.4635afa;1Gb0e;T 0.86 0.89 0 0 87.5 New splice site 7 bp downstream c.5312af9;1Gb0e;A 0.81 0.91 0 0 86.1 c.5836afa;2Ab0e;C 0.89 0.87 0 0 88 c.6387afa;1Gb0e;T 0.77 0.87 0 0 82 c.6479af9;1Gb0e;A 0.82 0.87 0 0 85 c.6479af9;1Gb0e;C 0.82 0.31 0 0 56.6 c.1100afa;6Tb0e;A 0 0 0.9 0.93 91.6 Creates new splice site c.351_352delAG p.S119fs Frameshift c.564delA p.E189Cfs Frameshift c.885delC p.L296Cfs Frameshift c.1374delA p.T459Qfs Frameshift c.3543delT p.K1182Rfs Frameshift c.3846delA p.G1283Dfs Frameshift c.4734delG p.L1580* Stop codon c.5932delA p.T1979Qfs Frameshift c.6317_6323del p.R2107_ GCCGCAT M2108delfs Frameshift c.121Gb0e;A p.W41* Stop codon c.318Tb0e;G p.Y106* Stop codon c.1906Cb0e;T p.Q636* Stop codon c.4639Ab0e;T p.K1547* Stop codon For SpliceSiteFinder and GeneSplicer, 1 is the highest score for splice site activity and 0 is the lowest.
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ABCA4 p.Thr1117Ile 21911583:120:1272
status: NEW[hide] The external limiting membrane in early-onset Star... Invest Ophthalmol Vis Sci. 2014 Aug 19;55(10):6139-49. doi: 10.1167/iovs.14-15126. Lee W, Noupuu K, Oll M, Duncker T, Burke T, Zernant J, Bearelly S, Tsang SH, Sparrow JR, Allikmets R
The external limiting membrane in early-onset Stargardt disease.
Invest Ophthalmol Vis Sci. 2014 Aug 19;55(10):6139-49. doi: 10.1167/iovs.14-15126., [PMID:25139735]
Abstract [show]
PURPOSE: To describe pathologic changes of the external limiting membrane (ELM) in young patients with early-onset Stargardt (STGD1) disease. METHODS: Twenty-six STGD1 patients aged younger than 20 years with confirmed disease-causing adenosine triphosphate-binding cassette, subfamily A, member 4 (ABCA4) alleles and 30 age-matched unaffected individuals were studied. Spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (AF), and color fundus photography (CFP) images, as well as full-field electroretinograms were obtained and analyzed for one to four visits in each patient. RESULTS: The ELM in all patients exhibited a distinct thickening that was not observed in unaffected individuals. In addition, accumulations of reflective deposits were noted in the outer nuclear layer in every patient. Four patients exhibited a concave protuberance or bulging of a thickened and hyperreflective ELM band within the fovea containing preserved photoreceptors. Longitudinal SD-OCT data in several patients revealed the persistence of this ELM abnormality over a period of time (1-4 years). Furthermore, the edges of the inner segment ellipsoid band appeared to recede earlier than the ELM band in active lesions. CONCLUSIONS: Structural changes seen in the ELM of this cohort may reflect a gliotic response to cellular stress at the photoreceptor level in early-onset STGD1.
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No. Sentence Comment
91 [L541P;A1038V] p.R1640W P15 16 Caucasian 20/200 (1.00) 20/200 (1.00) 2 n/a Mid-late 8 p.K346T p.T1117I P16 9 Caucasian 20/150 (0.88) 20/150 (0.88) 1 n/a 1 p.P1380L p.G1961E P17 18 Caucasian 20/40 (0.30) 20/150 (0.88) 1 1 Early 3 p.P1380L p.G1961E P18ߥ 18 Caucasian 20/150 (0.88) 20/150 (0.88) 2 1 Late 4 p.
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ABCA4 p.Thr1117Ile 25139735:91:96
status: NEW[hide] Flecks in Recessive Stargardt Disease: Short-Wavel... Invest Ophthalmol Vis Sci. 2015 Jul;56(8):5029-39. doi: 10.1167/iovs.15-16763. Sparrow JR, Marsiglia M, Allikmets R, Tsang S, Lee W, Duncker T, Zernant J
Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near-Infrared Autofluorescence, and Optical Coherence Tomography.
Invest Ophthalmol Vis Sci. 2015 Jul;56(8):5029-39. doi: 10.1167/iovs.15-16763., [PMID:26230768]
Abstract [show]
PURPOSE: We evaluated the incongruous observation whereby flecks in recessive Stargardt disease (STGD1) can exhibit increased short-wavelength autofluorescence (SW-AF) that originates from retinal pigment epithelium (RPE) lipofuscin, while near-infrared AF (NIR-AF), emitted primarily from RPE melanin, is usually reduced or absent at fleck positions. METHODS: Flecks in SW- and NIR-AF images and spectral-domain optical coherence tomography (SD-OCT) scans were studied in 19 STGD1 patients carrying disease-causing ABCA4 mutations. Fleck spatial distribution and progression were recorded in serial AF images. RESULTS: Flecks observed in SW-AF images typically colocalized with darkened foci in NIR-AF images; the NIR-AF profiles were larger. The decreased NIR-AF signal from flecks preceded apparent changes in SW-AF. Spatiotemporal changes in fleck distribution usually progressed centrifugally, but in one case centripetal expansion was observed. Flecks in SW-AF images corresponded to hyperreflective deposits that progressively traversed photoreceptor-attributable bands in SD-OCT images. Outer nuclear layer (ONL) thickness negatively correlated with expansion of flecks from outer to inner retina. CONCLUSIONS: In the healthy retina, RPE lipofuscin fluorophores form in photoreceptor cells but are transferred to RPE; thus the SW-AF signal from photoreceptor cells is negligible. In STGD1, NIR-AF imaging reveals that flecks are predominantly hypofluorescent and larger and that NIR-AF darkening occurs prior to heightened SW-AF signal. These observations indicate that RPE cells associated with flecks in STGD1 are considerably changed or lost. Spectral-domain OCT findings are indicative of ongoing photoreceptor cell degeneration. The bright SW-AF signal of flecks likely originates from augmented lipofuscin formation in degenerating photoreceptor cells impaired by the failure of RPE.
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No. Sentence Comment
48 [IVS15&#fe;1G>A 2 M 12.00 Caucasian 0.5 0.5 p. [L541P; A1038V] 3* M 9.00 Caucasian 1 1 p. [W855*]; [T1526M] 4 F 47.55 Caucasian 1.3 1.3 p. [L541P; A1038V]; [G1961E] 5* F 16.47 Caucasian 0.6 0.6 p. [T972N]; [L2027F] 6* M 16.98 Caucasian 1.3 1.3 p. [K346T]; [T1117I] 7 F 23.80 Caucasian 0.6 0.4 p. [R1161S] 8* F 28.67 Caucasian 1.3 1.3 p. [P1380L]; [P1380L] 9 M 42.83 Caucasian 0.9 0.4 c.
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ABCA4 p.Thr1117Ile 26230768:48:257
status: NEW[hide] Quantitative Fundus Autofluorescence and Optical C... Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371. Duncker T, Stein GE, Lee W, Tsang SH, Zernant J, Bearelly S, Hood DC, Greenstein VC, Delori FC, Allikmets R, Sparrow JR
Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.
Invest Ophthalmol Vis Sci. 2015 Nov 1;56(12):7274-85. doi: 10.1167/iovs.15-17371., [PMID:26551331]
Abstract [show]
PURPOSE: To assess whether carriers of ABCA4 mutations have increased RPE lipofuscin levels based on quantitative fundus autofluorescence (qAF) and whether spectral-domain optical coherence tomography (SD-OCT) reveals structural abnormalities in this cohort. METHODS: Seventy-five individuals who are heterozygous for ABCA4 mutations (mean age, 47.3 years; range, 9-82 years) were recruited as family members of affected patients from 46 unrelated families. For comparison, 57 affected family members with biallelic ABCA4 mutations (mean age, 23.4 years; range, 6-67 years) and two noncarrier siblings were also enrolled. Autofluorescence images (30 degrees , 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Horizontal SD-OCT scans through the fovea were obtained and the thicknesses of the outer retinal layers were measured. RESULTS: In 60 of 65 carriers of ABCA4 mutations (age range, 9-60), qAF levels were within normal limits (95% confidence level) observed for healthy noncarrier subjects, while qAF levels of affected family members were significantly increased. Perifoveal fleck-like abnormalities were observed in fundus AF images in four carriers, and corresponding changes were detected in the outer retinal layers in SD-OCT scans. Thicknesses of the outer retinal layers were within the normal range. CONCLUSIONS: With few exceptions, individuals heterozygous for ABCA4 mutations and between the ages of 9 and 60 years do not present with elevated qAF. In a small number of carriers, perifoveal fleck-like changes were visible.
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28 [L541P;A1038V] 0.10 0.10 OS n/a 141 S2.2 F 44.4 Indian Mother c.6729&#fe;5_&#fe;19del 0.10 0.00 OS 257 291 S2.3 M 56.2 Indian Father p.G1961E 0.00 0.00 OD 475 431 S3.4 F 54.1 White Mother p.G863A 0.00 0.00 OS 459 451 S3.5 F 82.0 White Grandmother p.G863A 0.00 0.00 OD n/a n/a S4.2 F 44.6 White Mother p.W855* 0.00 0.00 OD 330 n/a S4.3 M 40.9 White Father p.T1526M 0.00 0.00 OS 283 271 S5.2 F 71.5 White Sister p.C698Y 0.00 0.10 OD n/a n/a S5.3 F 67.5 White Sister c.2160&#fe;1G>C 0.00 0.00 OS n/a n/a S5.4 F 62.9 White Sister p.C698Y 0.00 0.00 OD n/a n/a S6.2 M 54.9 Black Brother p.T1526M 0.10 0.00 OS 477 423 S7.2 F 48.9 White Mother c.5196&#fe;1G>A 0.00 0.00 OS 443 415 S8.2 F 59.6 White Mother p.K346T 0.00 0.00 OD 546 483 S8.3 M 54.6 White Father p.T1117I 0.10 0.10 OD 289 n/a S9.2 F 51.5 White Mother c.5196&#fe;1137G>A 0.00 0.00 n/a 302 n/a S9.3 M 57.8 White Father p.C54Y 0.00 0.00 OS 419 375 S10.2 M 24.1 Indian Brother p.Q2220* 0.00 0.00 OD 227 227 S11.2 F 40.0 Asian Mother c.5923del 0.00 0.18 OD 229 191 S11.3 M 40.1 Asian Father p.R408* 0.00 0.00 OD 195 178 S12.2 F 53.2 White Mother p.L2027F 0.00 0.00 n/a 355 309 S13.2 F 49.8 White Mother p.R1161S 0.00 0.00 OS 367 372 S13.3 M 22.3 White Brother p.R1161S 0.00 0.00 OD 202 206 S14.2 F 67.0 White Mother p.P1380L 0.00 0.00 OD n/a n/a S14.3 F 24.4 White Sister p.P1380L 0.00 0.00 OS n/a 163 S15.3 F 26.8 White Sister c.3050&#fe;5G>A 0.00 0.00 n/a 293 281 S16.2 M 53.7 Black Father c.4253&#fe;5G>T 0.00 0.00 n/a n/a 204 S17.2 F 60.0 Hispanic Mother p.A1038V 0.00 0.00 n/a 247 n/a S18.2 F 41.8 Indian Father c.5917del 0.00 0.00 OD n/a 194 S18.3 M 48.6 Indian Mother c.859-9T>C 0.00 0.00 OD 253 215 S18.4 F 12.9 Indian Sister c.5917del 0.00 0.00 OD 84 93 S19.4 F 58.5 White Mother p.L2027F 0.00 0.00 OD 205 n/a S19.5 M 61.6 White Father p.G851D 0.10 0.10 OD n/a n/a S20.2 F 41.5 White Mother c.5312&#fe;1G>A 0.00 0.00 n/a 335 351 S20.3 M 39.0 White Father p.R2030* 0.00 0.10 n/a 442 n/a S21.3 F 53.1 White Mother p.G1961E 0.00 0.00 OD 490 488 S22.3 M 46.3 White Father p.L2027F 0.00 0.00 OS 386 376 S22.4 F 47.1 White Mother p.
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ABCA4 p.Thr1117Ile 26551331:28:754
status: NEW67 [L541P;A1038V] c.768&#fe;358C>T 0.30 0.18 n/a 413 P 2.1ߤ M 17.9 Indian p.G1961E c.6729&#fe;5_&#fe;19del 0.70 0.88 340 363 P 3.1&#a7; F 25.1 White p.G863A c.5898&#fe;1G>A 0.80 0.80 710 675 P 3.2ߤ F 18.9 White p.G863A c.5898&#fe;1G>A 0.00 0.00 465 431 P 3.3 F 24.4 White p.G863A c.5898&#fe;1G>A 0.18 0.00 507 467 P 4.1 M 9.0 White p.W855* p.T1526M 1.00 1.00 538 n/a P 5.1 F 67.0 White p.C54Y c.2160&#fe;1G>C CF HM n/a n/a P 6.1 M 46.0 Black p.T1526M 0.30 0.80 n/a n/a P 7.1 F 25.3 White c.5196&#fe;1G>A p.S2235P 1.00 1.30 420 317 P 8.1 M 17.0 White p.K346T p.T1117I 1.30 0.70 871 828 P 9.1 M 21.5 White p.C54Y c.5196&#fe;1137G>A 0.18 0.18 609 608 P 10.1 M 31.0 Indian c.
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ABCA4 p.Thr1117Ile 26551331:67:569
status: NEW