ABCA4 p.Arg1443Gln
| ClinVar: |
c.4328G>A
,
p.Arg1443His
?
, not provided
|
| Predicted by SNAP2: | A: D (71%), C: D (71%), D: D (71%), E: D (71%), F: D (75%), G: D (71%), H: D (85%), I: D (71%), K: N (57%), L: D (71%), M: D (71%), N: D (53%), P: D (75%), Q: D (59%), S: D (59%), T: D (53%), V: D (71%), W: D (85%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Targeted Next-Generation Sequencing Improves the D... Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2173-82. doi: 10.1167/iovs.14-16178. Fernandez-San Jose P, Corton M, Blanco-Kelly F, Avila-Fernandez A, Lopez-Martinez MA, Sanchez-Navarro I, Sanchez-Alcudia R, Perez-Carro R, Zurita O, Sanchez-Bolivar N, Lopez-Molina MI, Garcia-Sandoval B, Riveiro-Alvarez R, Ayuso C
Targeted Next-Generation Sequencing Improves the Diagnosis of Autosomal Dominant Retinitis Pigmentosa in Spanish Patients.
Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2173-82. doi: 10.1167/iovs.14-16178., [PMID:25698705]
Abstract [show]
PURPOSE: Next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in retinal dystrophies, a group of inherited diseases that are highly heterogeneous. Therefore, the aim of this study is the application of an NGS-based approach in a Spanish cohort of autosomal dominant retinitis pigmentosa (RP) patients to find out causative mutations. METHODS: Index cases of 59 Spanish families with initial diagnosis of autosomal dominant RP and unsuccessfully studied for mutations in the most common RP causal genes, were selected for application of a NGS-based approach with a custom panel for 73 genes related to retinal dystrophies. Candidate variants were select based on frequency, pathogenicity, inherited model, and phenotype. Subsequently, confirmation by Sanger sequencing, cosegregation analysis, and population studies, was applied for determining the implication of those variants in the pathology. RESULTS: Overall 31 candidate variants were selected. From them, 17 variants were considered as mutations causative of the disease, 64% (11/17) of them were novel and 36% (6/17) were known RP-related mutations. Therefore, applying this technology16 families were characterized rendering a mutation detection rate of 27% (16/59). Of them, 5% (3/59) of cases displayed mutations in recessive or X-linked genes (ABCA4, RPGR, and RP2) allowing a genetic and clinical reclassification of those families. Furthermore, seven novel variants with uncertain significance and seven novel variants probably not causative of disease were also found. CONCLUSIONS: This NGS strategy is a fast, effective, and reliable tool to detect known and novel mutations in autosomal dominant RP patients allowing genetic reclassification in some cases and increasing the knowledge of pathogenesis in retinal dystrophies.
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No. Sentence Comment
79 Spectrum of Variants Causative of the Disease Identified With the RD_NGS_Panel in Autosomal Dominant Retinitis Pigmentosa Families Family Gene NM HGVS-cdna HGVS-prot Effect Zyg dbSNP (MAF) SIFT Polyphen-2 Mutation Taster Human Splicing Finder Cosegregation (Affected/ Unaffected/ Asymptomatic) Frequency in Spanish Control Alleles Reference Known mutations RP-1875 ABCA4* NM_000350.2 c.3386G>T p.Arg1129Leu Missense Het rs1801269 (<0.01) D (0) Pr-D (0.992) DC (1.000) - Yes (2/11 ) 0/150 Allikmets et al., 28 1997 c.6148G>C p.Val2050Leu Missense Het rs41292677 (0.04) D (0.01) Pr-D (0.950) DC (0.999) - 0/150 Allikmets et al., 29 1997 RP-1688 CRX NM_000554.4 c.586_587insC p.Ala198Glyfs*38 Frameshift Het - - - DC (1.000) - NA 0/150 Sohocki et al., 30 1998 RP-1970 PRPF31 NM_015629.3 c.1146&#fe;2T>C - Splicing Het - - - DC (1.000) Decrease 5 0 donor site of exon 11 (90.88->72.59) Yes (2) 0/150 Waseem et al., 31 2007 RP-0642 RHO NM_000539.3 c.44A>G p.Asn15Ser Missense Het rs104893786 (nfd) D (0) Pr-D (0.998) DC (1.000) - Yes (1/2) 0/150 Kranich et al., 32 1993 RP-1480 SNRNP200 NM_014014.4 c.3260C>T p.Ser1087Leu Missense Het - D (0) Pr-D (0.995) DC (1.000) - Yes (4/4/4) 0/150 Zhao et al., 33 2009 Novel LOF protein mutations RP-1541 PRPF31 NM_015629.3 c.937_938insA p.Gly314Argfs*10 Frameshift Het - - - DC (1.000) - Yes (2/2) 0/150 This study RP-1176 PRPH2 NM_000322.4 c.582-1G>A - Splicing Het - - - - Decrease 3 0 acceptor site of exon 2 (82.97->54.03) Yes (2) 0/150 This study RP-2072 RP1 NM_006269.1 c.1981G>T p.Glu661* Nonsense Het - - - DC (1.000) - NA 0/150 This study RP-1890 RP1 NM_006269.1 c.2286delA p.Asn763Ilefs*12 Frameshift Het - - - DC (1.000) - Yes (2) 0/150 This study RP-1387 RP1 NM_006269.1 c.2745_2749del p.Tyr915* Nonsense Het - - - DC (1.000) - Yes (4/2) 0/150 This study RP-0631 RPGR* NM_000328.2 c.1234C>T p.Arg412* Nonsense Het - - - DC (1.000) - Yes (2) 0/150 This study Novel nonsynonymous/in-frame mutations RP-1728 GUCA1B NM_002098.5 c.131G>A p.Arg44His Missense Het - D (0.004) B (0.065) DC (0.997) - Yes (2/1) 0/300 This study RP-0422 IMPDH1 NM_000883.3 c.962C>T p.Ala321Val Missense Het - D (0) Pr-D (0.926) DC (1.000) - Yes (3/11) 0/300 This study RP-0652 PRPH2 NM_000322.4 c.536G>T p.Trp179Leu Missense Het - D (0.010) Pr-D (1.000) DC (1.000) - Yes (2) 0/300 This study RP-0948 RP1 NM_006269.1 c.4328G>A p.Arg1443Gln Missense Het - D (0) Pr-D (0.974) P (0.993) - Yes (2/1) 0/300 This study RP-1682 RP2* NM_006915.2 c.9_11del p.Phe4del In-frame Het - - - DC (0.986) - Yes (1/3) 0/300 This study LOF, loss of function; Zyg, zygosity; Het, heterozygosis; nfd, no frequency data; SIFT, deleterious (D); Polyphen2: probably damaging (Pr-D) and benign (B); Mutation Taster: disease causing (DC) and polymorphism (P); NA, not available.
X
ABCA4 p.Arg1443Gln 25698705:79:2348
status: NEW81 al), PRPH2 (p.Trp179Leu), and RP1 (p.Arg1443Gln).
X
ABCA4 p.Arg1443Gln 25698705:81:37
status: NEW