ABCA4 p.Thr2240Ala
| Predicted by SNAP2: | A: N (61%), C: N (53%), D: N (57%), E: N (61%), F: D (63%), G: N (53%), H: N (72%), I: N (53%), K: N (72%), L: N (53%), M: N (53%), N: N (78%), P: N (53%), Q: N (61%), R: N (57%), S: N (82%), V: N (61%), W: D (75%), Y: D (59%), |
| 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, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Molecular testing for hereditary retinal disease a... Arch Ophthalmol. 2007 Feb;125(2):252-8. Downs K, Zacks DN, Caruso R, Karoukis AJ, Branham K, Yashar BM, Haimann MH, Trzupek K, Meltzer M, Blain D, Richards JE, Weleber RG, Heckenlively JR, Sieving PA, Ayyagari R
Molecular testing for hereditary retinal disease as part of clinical care.
Arch Ophthalmol. 2007 Feb;125(2):252-8., [PMID:17296903]
Abstract [show]
OBJECTIVE: To describe clinical molecular testing for hereditary retinal degenerations, highlighting results, interpretation, and patient education. METHODS: Mutation analysis of 8 retinal genes was performed by dideoxy sequencing. Pretest and posttest genetic counseling was offered to patients. The laboratory report listed results and provided individualized interpretation. RESULTS: A total of 350 tests were performed. The molecular basis of disease was determined in 133 of 266 diagnostic tests; the disease-causing mutations were not identified in the remaining 133 diagnostic tests. Predictive and carrier tests were requested for 9 and 75 nonsymptomatic patients with known familial mutations, respectively. CONCLUSIONS: Molecular testing can confirm a clinical diagnosis, identify carrier status, and confirm or rule out the presence of a familial mutation in nonsymptomatic at-risk relatives. Because causative mutations cannot be identified in all patients with retinal diseases, it is essential that patients are counseled before testing regarding the benefits and limitations of this emerging diagnostic tool. CLINICAL RELEVANCE: The molecular definition of the genetic basis of disease provides a unique adjunct to the clinical care of patients with hereditary retinal degenerations.
Comments [show]
None has been submitted yet.
No. Sentence Comment
86 Novel Sequence Changes Gene* Nucleotide Change Amino Acid Change Potentially Pathogenic Changes ABCA4 164A → C H55P 611G → A A204T 868C → T R290W 1699G → A V567M 1726G → C D576H 1817G → A G606A 1964T → G L725I 2173C → A F655C 2297G → A G766D 2385C → G S795R 2401G→ A A801T 3076T → C F1026L 3138T → G L1046W 3414T → C L1138P 4256T → C M1419T 4535C → A P1512H 4849G → A V1617M 4870T → G W1624G 5026A → C T1676P IVS36 - 3G→ C Splice site change 5701C → A F1900L 5885T → A V1962D 6718A → G T2240A IVS42 ϩ 1G → A Intronic change RDS 667G → C C222S VMD2 174A → G Y29C 660T → C L191P 738G → T L217F 948G → A W287X 974A → G N296D Potentially Neutral Polymorphic Changes or Changes of Uncertain Significance ABCA4 320C → A R107R 1692A → G P562P 2823T → C C941C 4869C → G G1623G 5318C → T A1773V† 5390T → C C1797C IVS15 - 13T → C Intronic change IVS24 ϩ 46A → T Intronic change IVS35 ϩ 8G → A Intronic change IVS40 - 35A → C Intronic change IVS47 ϩ 29T → C Intronic change IVS50 - 131ins/del Intronic change EFEMP1 399C → A G133G RDS IVS3 ϩ 13C → T Intronic change *The genes are described in the second footnote to Table 1.
X
ABCA4 p.Thr2240Ala 17296903:86:624
status: NEWX
ABCA4 p.Thr2240Ala 17296903:86:647
status: NEW[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.
Comments [show]
None has been submitted yet.
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.
X
ABCA4 p.Thr2240Ala 21911583:120:2193
status: NEW