ABCA4 p.Arg290Trp
| ClinVar: |
c.870G>A
,
p.Arg290=
?
, Uncertain significance
|
| Predicted by SNAP2: | A: D (80%), C: D (80%), D: D (80%), E: D (80%), F: D (85%), G: D (80%), H: D (71%), I: D (80%), K: D (59%), L: D (80%), M: D (80%), N: D (66%), P: D (80%), Q: D (71%), S: D (71%), T: D (63%), V: D (80%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: N, F: D, G: D, H: N, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, S: N, T: N, V: N, W: D, Y: D, |
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[hide] ABCA4 mutations in Portuguese Stargardt patients: ... Mol Vis. 2009;15:584-91. Epub 2009 Mar 25. Maia-Lopes S, Aguirre-Lamban J, Castelo-Branco M, Riveiro-Alvarez R, Ayuso C, Silva ED
ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis.
Mol Vis. 2009;15:584-91. Epub 2009 Mar 25., [PMID:19365591]
Abstract [show]
PURPOSE: To resolve the spectrum of causative retina-specific ATP-binding cassette transporter gene (ABCA4) gene mutations in Portuguese Stargardt (STGD) patients and compare allele frequencies obtained in this cohort with those of previous population surveys. METHODS: Using a microarray technique (ABCR400 gene chip), we screened all previously reported ABCA4 gene mutations in the genomic DNA of 27 patients from 21 unrelated Stargardt families whose phenotypes had been clinically evaluated using psychophysics and electrophysiological measurements. Furthermore, we performed denaturing high performance liquid chromatography whenever one or both mutant alleles failed to be detected using the ABCR gene chip. RESULTS: A total of 36 mutant alleles (out of the 54 tested) were identified in STGD patients, resulting in a detection rate of 67%. Two mutant alleles were present in 12 out of 21 STGD families (57%), whereas in four out of 21 (19%) of the families, only one mutant allele was found. We report the presence of 22 putative pathogenic alterations, including two sequence changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease-associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X). The great majority of the mutations were missense (72.7%). Seven frameshift variants (19.4%), three nonsense mutations (8.3%), and one splicing sequence change (2.7%) were also found in STGD chromosomes. The most prevalent pathologic variant was the missense mutation p.Leu11Pro. Present in 19% of the families, this mutation represents a quite high prevalence in comparison to other European populations. In addition, 23 polymorphisms were also identified, including four novel intronic sequence variants. CONCLUSIONS: To our knowledge, this study represents the first report of ABCA4 mutations in Portuguese STGD patients and provides further evidence of different mutation frequency across populations. Phenotypic characterization of novel putative mutations was addressed.
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No. Sentence Comment
63 [Met1Val]+ [Arg2030Gln], found in 4.8% of the families (for details, see Table 1).
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ABCA4 p.Arg290Trp 19365591:63:104
status: NEW64 Most of the mutations detected have been reported as STGD-associated variants: p.Met1Val, p.Asn96Asp, p.Arg290Trp, p.Val931Met, p.Gly1961Glu, p.Leu2027Phe, p.Arg2030Gln, p.Asp1048fs, and IVS40+5G>A.
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ABCA4 p.Arg290Trp 19365591:64:104
status: NEW69 4139C>T(28) p.Asn96Asp [30]/p.Pro1380Leu [13] 2 4458 Mi 5 8/10 / 6/10 ND / ND ND/ND 4455 S 8 1/10 / 8/10 ND / ND ND/ND 3 4431 Mo 6 1,6/10 / 1,6/10 c.1804C>T(13) / c.IVS+5G>A(40) p.Arg602Trp [30]/SPLICE [11] 4 4626 S 6 FC / FC c.3211_3212insGT(22) / c.3211_3212insGT(22) p.Asp1048fs [5]/p.Asp1048fs [5] 5 4514 S 12 1/10 / 1/10 c.32T>C(1) / c.
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ABCA4 p.Arg290Trp 19365591:69:120
status: NEW70 [1A>G(1)]+[6089G>A(44)] p.Leu11Pro [12]/p.(Met1Val [6])+(Arg2030Gln [9]) 6 4525 Mo 14 1/10 / 1/10 ND / c.868C>T(8) ND/p.Arg290Trp [6] 7 4585 Mo 11 0.5/10 / 0.5/10 c.6079C>T(44) / ND p.Leu2027Phe [5]/ND 8 4678 Mo 9 0.5/10 / 1/10 c.3113C>T(21) / c.3602T>G(24) p.Ala1038Val [5]/p.Leu1201Arg [9] 9 4675 Mo 7 0.5/10 / 1/10 c.2T<C(1) / c.2T<C(1) p.Met1Thr/p.Met1Thr 10 4737 Mo 24 1.2/10 / 1.2/10 c.5882G>A(42) / c.3211_3212insGT(22) p.Gly1961Glu [4]/p.Asp1048fs 11 4613 S 9 FC / FC c.
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ABCA4 p.Arg290Trp 19365591:70:120
status: NEW[hide] Evidence of widespread retinal dysfunction in pati... Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1191-9. Maia-Lopes S, Silva ED, Silva MF, Reis A, Faria P, Castelo-Branco M
Evidence of widespread retinal dysfunction in patients with stargardt disease and morphologically unaffected carrier relatives.
Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1191-9., [PMID:18326749]
Abstract [show]
PURPOSE: To characterize contrast sensitivity (CS) across the visual field for two achromatic spatial-temporal frequencies in 21 families with Stargardt disease (STGD) and to correlate psychophysical impairment with patterns of change in multifocal electroretinography (mfERG). METHODS: Twenty-seven eyes from patients with STGD, 16 eyes from asymptomatic relatives, and 44 age-matched control eyes were included. Chromatic CS function was assessed by comparing protan, deutan, and tritan (Cambridge Color Test; Cambridge Research Systems Ltd., Rochester, UK) and anomaloscope measures (IF-2; Roland Consult, Wiesbaden, Germany). Achromatic CS measures were obtained with custom-made software in nine locations by using randomly interleaved staircases. The first task-low spatial frequency (LSF)-matched the known frequency-doubling method that is believed to activate the magnocellular pathway preferentially. The second included an intermediate spatial frequency (ISF, 3.5 cyc/deg). mfERGs (RETIscan; Roland Consult) were also obtained. Relatives were screened for ABCA4 mutations by ABCR400 microarray and direct sequencing. RESULTS: Central impairment of achromatic and chromatic CS (along the three isolation axes) was observed in STGD. LSF and ISF tasks revealed significant and widespread dysfunction in patients and their morphologically unaffected relatives, 80% of whom were found to be ABCA4 mutation carriers. Significant reduction of P1 amplitudes was also observed in both groups. CONCLUSIONS: CS function is impaired in patients with STGD at distinct spatial-temporal frequencies, which, in addition to the color vision deficits, suggests dual impairment of the magno- parvocellular pathways. STGD morphologically unaffected carriers may show patterns of psychophysical dysfunction that are mirrored by abnormal mfERG responses.
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150 Several other sequence changes that have been significantly correlated to the STGD phenotype (M1V, N96D, R290W, L2027F, R2030Q, V2050L, 3211insGT, and IVS40ϩ5GϾA) were also identified.
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ABCA4 p.Arg290Trp 18326749:150:105
status: NEW134 Several other sequence changes that have been significantly correlated to the STGD phenotype (M1V, N96D, R290W, L2027F, R2030Q, V2050L, 3211insGT, and IVS40af9;5Gb0e;A) were also identified.
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ABCA4 p.Arg290Trp 18326749:134:105
status: NEW[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.
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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.
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ABCA4 p.Arg290Trp 17296903:86:158
status: NEW[hide] ABCA4 mutational spectrum in Mexican patients with... Exp Eye Res. 2013 Apr;109:77-82. doi: 10.1016/j.exer.2013.02.006. Epub 2013 Feb 16. Chacon-Camacho OF, Granillo-Alvarez M, Ayala-Ramirez R, Zenteno JC
ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation.
Exp Eye Res. 2013 Apr;109:77-82. doi: 10.1016/j.exer.2013.02.006. Epub 2013 Feb 16., [PMID:23419329]
Abstract [show]
The aim of this study was to assess the mutational spectrum of the ABCA4 gene in a cohort of patients with Stargardt disease from Mexico, a previously uncharacterized population. Clinical diagnosis in each patient was supported by a complete ophthalmological assessment that included visual acuity measurement, a slit lamp examination, a fundus examination and photography, electroretinography, fluorescein angiography, and computerized visual fields testing. Molecular analysis was performed by PCR amplification and direct nucleotide sequence of the 50 exons of the ABCA4 gene in genomic DNA. A total of 31 unrelated subjects with the disease were enrolled in the study. Molecular analysis in the total group of 62 alleles allowed the identification of 46 mutant ABCA4 alleles carrying 29 different pathogenic disease-associated mutations. Two ABCA4 mutant alleles were detected in 20 of the 31 patients (64.5%), a single disease allele was identified in six (19.4%), and no mutant alleles were detected in five of the cases (16.1%). Most patients with two ABCA4 mutations (11/20, 55%) were compound heterozygotes. Twelve variants were novel ABCA4 mutations. Nucleotide substitutions were the most frequent type of variation, occurring in 26 out of 29 (89.7%) different mutations. The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. The identification of recurrent mutations in our cohort will direct future ABCA4 molecular screening in patients from this ethnic group.
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100 Allele 1 Allele 2 Genotype Exon Nucleotide change Polypeptide change Exon Nucleotide change Polypeptide change Familial case # 1 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 2 e NI e e NI e e 3 6 c.634C>T p.R212C (D) 38 c.5318C>T p.A1773V (D) Compound heterozygous 4 23 c.3386G>T p.R1129L (D) 28 c.4139C>T p.P1380L (D) Compound heterozygous 5 e NI e e NI e e 6 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 7 e NI e e NI e e 8 16 c.2453G>A p.G818E (D) 28 c.4249_4251 delTTC p.F1417del (D; N) Compound heterozygous 9 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous Sporadic case # 1 8 c.868C>T p.R290W (D) e IVS8&#fe;1G>A Splicing (D; N) Compound heterozygous 2 38 c.5318C>T p.A1773V (D) - NI - Heterozygous 3 20 c.3041T>G p.L1014R (D) 1; 49 c.52C>T; c.6764G>T p.R18W (D); p.S2255I (B) Compound heterozygous 4 13; 19 c.1804C>T; c.2828G>A p.R602W (D); p.R943Q (U) 16 c.2453G>A p.G818E (D) Compound heterozygous 5 38 c.5324T>A p. I1775N (D; N) 38 c.5324T>A p.I1775N (D; N) Homozygous 6 e NI e e NI e e 7 49 c.6764G>T p.S2255I (B) 49 c.6764 G>T p.S2255I (B) Homozygous 8 19; 40 c.2828 G>A; c.5503A>T p.R943Q (U); p.N1868I (U) 3 c.265G>T p.E89* (D; N) Compound heterozygous 9 38 c.5335T>C p.Y1779H (D;N) 38 c.5335T>C p.Y1779H (D;N) Homozygous 10 16 c.2453G>A p.G818E (D) 16 c.2453G>A p.G818E (D) Homozygous 11 6 c.723A>T p.E241D (D;N) 36 c.5114G>A p.R1705Q (D) Compound heterozygous 12 2 c.71G>A (D) p.R24H e NI e Heterozygous 13 30 c.4537_4538insC p.Q1513Pfs*41 (D; N) e NI e Heterozygous 14 32 c.4667G>C p.R1556T (D; N) 32 c.4667G>C p.R1556T (D; N) Homozygous 15 45 c.6221G>T p.G2074V (D; N) 16 c.2453G>A p.G818E (D) Compound heterozygous 16 16; 41 c.2453G>A; c.5824G>C p. G818E (D); p. E1942Q (B;N) 46 c.6384A>G p.H2128R (D) Compound heterozygous 17 16 c.2453G>A p. G818E (D) e NI e Heterozygous 18 32 c.4653G>A p. W1551* (D; N) e NI e Heterozygous 19 23 c.3386G>T p. R1129L (D) e NI e Heterozygous 20 36 c.5045_5059del GTTGCCATCTGCGTG p.V1682_ V1686del (D; N) 29; 49 c.4328G>A; c.6764G>T p.R1443H (D); p.S2255I (B) Compound heterozygous 21 19 c.2894A>G p.N965S (D) 19 c.2894A>G p.N965S (D) Homozygous 22 e NI e e NI e e STGD accounts for approximately 7% of all retinal dystrophies; it is one of the most common genetic forms of juvenile or early adult onset macular degeneration.
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ABCA4 p.Arg290Trp 23419329:100:645
status: NEW119 ABCA4 Exon # Nucleotide change Predicted protein effect Number of alleles Population genotypic frequency in EVS Population allelic frequency in EVS (%) 1 c.52C>T p.R18W 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 2 c.71G>A p.R24H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 3 c.265G>T p.E89* (N) 1 NR NR 6 c.634C>T p.R212C 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 6 c.723A>T p.E241D (N) 1 NR NR 8 c.868C>T p.R290W 1 NR NR IVS8 IVS8 &#fe; 1G>A Splicing mutation (N) 1 NR NR 13 c.1804C>T p.R602W 1 NR NR 16 c.2453G>A p.G818E 7 NR NR 19 c.2828G>A p.R943Q 2 AA &#bc; 8/AG &#bc; 400/GG &#bc; 6095 A &#bc; 3.199/G &#bc; 96.801 19 c.2894A>G p.N965S 2 GG &#bc; 0/GA &#bc; 1/AA &#bc; 6502 G &#bc; 0.008/A &#bc; 99.992 20 c.3041T>G p.L1014R 1 NR NR 23 c.3386G>T p.R1129L 2 NR NR 28 c.4139C>T p.P1380L 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 28 c.4249_4251del TTC p.F1417del (N) 1 NR NR 29 c.4328G>A p.R1443H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 30 c.4537_4538insC p.Q1513Pfs*41 (N) 1 NR NR 32 c.4653G>A p.W1551* (N) 1 NR NR 32 c.4667G>C p.R1556T (N) 2 NR NR 36 c.5044_5058del GTTGCCATCTGCGTG p.V1682_V1686del (N) 1 NR NR 36 c.5114G>A p.R1705Q 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 38 c.5318C>T p.A1773V 8 NR NR 38 c.5324T>A p.I1775N (N) 2 NR NR 38 c.5335T>C p.Y1779H (N) 2 NR NR 40 c.5503A>T p.N1868I 1 TT &#bc; 16/TA &#bc; 589/AA &#bc; 5898 T &#bc; 4.775/A &#bc; 95.225 41 c.5824G>C p.E1942Q (N) 1 NR NR 45 c.6221G>T p.G2074V (N) 1 NR NR 46 c.6384A>G p.H2128R 1 NR NR 49 c.6764G>T p.S2255I 4 TT &#bc; 516/TG &#bc; 1473/GG &#bc; 4514 T &#bc; 19.26/G &#bc; 80.74 gold standard for ABCA4 mutational screening.
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ABCA4 p.Arg290Trp 23419329:119:480
status: NEW[hide] Distinct characteristics of inferonasal fundus aut... Invest Ophthalmol Vis Sci. 2013 Oct 17;54(10):6820-6. doi: 10.1167/iovs.13-12895. Duncker T, Lee W, Tsang SH, Greenberg JP, Zernant J, Allikmets R, Sparrow JR
Distinct characteristics of inferonasal fundus autofluorescence patterns in stargardt disease and retinitis pigmentosa.
Invest Ophthalmol Vis Sci. 2013 Oct 17;54(10):6820-6. doi: 10.1167/iovs.13-12895., [PMID:24071957]
Abstract [show]
PURPOSE: To report distinct characteristics of fundus autofluorescence (AF) patterns inferior to the optic disc in recessive Stargardt disease (STGD1) and retinitis pigmentosa (RP). METHODS: Short-wavelength (SW) and near-infrared (NIR) AF images were acquired from patients with STGD1 and RP. In SW- and NIR-AF images of STGD1 patients, gray levels (GL) on both sides of the demarcation line were measured. RESULTS: In STGD1, a demarcation line, which has been assigned to the closed optic fissure, was visible on SW-AF and NIR-AF inferior to the optic disc. In healthy subjects, this demarcation line is only visible by SW-AF. At 20 degrees inferior to the disc center, AF levels on the nasal side were 25% (+/-11%) lower than on the temporal side in SW-AF images and 18% (+/-11%) lower in NIR-AF images. For both STGD1 and RP, the inferonasal quadrant exhibited distinct SW- and NIR-AF patterns compared with other fundus areas. Disease-related AF changes, such as flecks, appeared to respect the demarcation line as a boundary. CONCLUSIONS: Disease-related AF patterns originating in RPE in STGD1 and RP appear to respect the demarcation line in the inferonasal quadrant of the fundus as a border. The visibility of the inferonasal demarcation line by NIR-AF in STGD1 but not in healthy eyes may indicate that increased levels of RPE lipofuscin modulate the melanin-related NIR-AF signal. This feature of NIR-AF images may aid in the diagnosis of STGD1 patients.
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51 Summary of Demographic, Clinical, and Genetic Data Patient Condition ABCA4 Mutations Sex Age, y Eye Iris Color Race/Ethnicity BCVA Snellen (logMAR) P1 STGD1 p.P1380L, p.G1961E M 12 OS Blue White 20/100 (0.70) P2 STGD1 p.P1380L, p.G1961E F 17 OS Brown White 20/150 (0.88) P3 STGD1 p.Q1003X, p.G1961E M 25 OS Brown White 20/40 (0.30) P4 STGD1 p.C54Y F 48 OD Blue White 20/30 (0.20) P5 STGD1 p.R2077W F 52 OD Blue White 20/40 (0.30) P6 STGD1 p.[L541P;A1038V] M 13 OS Brown White 20/150 (0.88) P7 STGD1 p.T972N, p.L2027F F 14 OS Blue White 20/80 (0.60) P8 STGD1 c.4537_4538insC, p.V1686M M 49 OS Brown White 20/50 (0.40) P9 STGD1 p.R1108H, p.P1380L M 50 OS Blue White 20/200 (1.00) P10 STGD1 c.5714&#fe;5G>A F 34 OD Blue White 20/200 (1.00) P11 STGD1 p.Q636H, p.G1961E M 46 OD Brown Indian 20/400 (1.30) P12 STGD1 c.5461-10T>C M 35 OD Brown Black 20/400 (1.30) P13 STGD1 p.R1640W F 20 OD Brown Black 20/125 (0.80) P14 STGD1 p.R290W M 47 OS Brown White 20/40 (0.30) P15 STGD1 p.A1773V, p.G1961E M 18 OD Brown White 20/150 (0.88) P16 AD RP p.T17M* F 23 OD Brown Hispanic 20/30 (0.20) P17 AD RP N/A M 39 OS Brown White 20/20 (0.00) P18 AR RP N/A M 50 OS Green White 20/20 (0.00) AD, autosomal dominant; AR, autosomal recessive; BCVA, best corrected visual acuity; F, female; logMAR, logarithm of the minimum angle of resolution; M, male; N/A, not available.
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ABCA4 p.Arg290Trp 24071957:51:922
status: NEW