ABCB6 p.Arg192Gln
| ClinVar: |
c.575G>A
,
p.Arg192Gln
?
, Uncertain significance
|
| Predicted by SNAP2: | A: D (80%), C: D (75%), D: D (91%), E: D (85%), F: D (91%), G: D (85%), H: D (75%), I: D (85%), K: D (59%), L: D (85%), M: D (80%), N: D (71%), P: D (91%), Q: D (80%), S: D (75%), T: D (80%), V: D (85%), W: D (91%), Y: D (91%), |
| 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: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Exome sequencing in developmental eye disease lead... Eur J Hum Genet. 2014 Jul;22(7):907-15. doi: 10.1038/ejhg.2013.268. Epub 2013 Nov 27. Prokudin I, Simons C, Grigg JR, Storen R, Kumar V, Phua ZY, Smith J, Flaherty M, Davila S, Jamieson RV
Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.
Eur J Hum Genet. 2014 Jul;22(7):907-15. doi: 10.1038/ejhg.2013.268. Epub 2013 Nov 27., [PMID:24281366]
Abstract [show]
Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/microphthalmia.
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No. Sentence Comment
62 In Patient 1 (Family 1, II.1), we detected a heterozygous mutation in gap junction alpha-8 (GJA8), c. 593G4A, predicting a deleterious substitution of arginine by glutamine (p.(Arg198Gln)), which segregated with disease in the family (Table 2, Figure 3a, Supplementary Figure S2), and is previously reported in autosomal-dominant cataract/microcornea.26 In Patient 4 (Family 4, II.1), a novel heterozygous variant was detected in CRYGC, Table 1 Clinical phenotypes and causative and other prioritised variants from exome sequencing in patients with developmental eye disease Sample (family, pedigree ID, inheritance patterna) Ocular phenotype Genes with causative variants:b,c,d prioritised variants with appropriate family segregation Genes with prioritised variants,c,d but lacking appropriate family segregation Novel Congenital cataracts and microcornea/microphthalmia Patient 1 (Family 1, II.1, AD) Nuclear cataracts, microcornea GJA8, c.593G4A, p.(Arg198Gln) Nil Devi and Vijayalakshmi,26 Patient 2 (Family 2, II.1, AD) Nuclear cataracts, microcornea Nil Nil - Patient 3 (Family 3, II.1) Cataracts, microcornea, iris processes to lens Nil CRYBA1, c.475G4A, p.(Gly159Ser) rs117757092 Patient 4e (Family 4, I.2, AD) Nuclear cataracts, microphthalmia CRYGC, c.497C4T, p.(Ser166Phe) Nil Yes Peters anomaly Patient 5 (Family 5, II.1) Peters anomaly, anterior polar cataracts CYP1B1, c.1200_1209dup, p.(Thr404Serfs*30) CYP1B1, c.171G4A, p.(Trp57*) Nil Stoilov et al,27 Vincent et al,6 Patient 6 (Family 6, II.1) Peters anomaly, rudimentary lens PAX6, c.152G4T, p.(Gly51Val) Nil Yes Patient 7 (Family 7, II.2) Peters anomaly, microphthalmia Nil Nil - Coloboma and microphthalmia Patient 8 (Family 8, II.1) Coloboma, limbal dermoid, anterior polar cataract Nil Nil - Patient 9 (Family 9, II.1, AR) Iris and fundal colobomas, microphthalmia Nil CYP1B1, c.868dup, p.(Arg290Profs*37) CYP1B1, c.241T4A, p.(Tyr81Asn) BFSP1, c.1620_1621del, p.(*541Lysext*7) Yes rs9282671 recorded in 1000G Patient 10 (Family 10, II.1) Iris and fundal colobomas Nil ABCB6, c.575G4A, p.(Arg192Gln) SLC16A12, c.472T4C, p.(Ser158Pro) rs150221689 rs150800688 Patient 11 (Family 11, II.1) Iris and fundal colobomas, microphthalmia Nil GDF3, c.974C4T, p.(Pro325Leu) CYP1B1, c.1103G4A, p.(Arg368His) CYP1B1, c.685G4A, p.(Glu229Lys) BFSP1, c.401G4C, p.(Cys134Ser) Yes rs79204362 rs57865060 Yes Abbreviations: AD, autosomal dominant, AR, autosomal recessive; Nil, no variant identified.
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ABCB6 p.Arg192Gln 24281366:62:2061
status: NEW91 Other patients with microphthalmia and coloboma have been found to have heterozygous missense variants in the TGF-beta domain of GDF3, and variable penetrance has been previously noted.30 In Patient 10 (Family 10, II.1), we detected a rare heterozygous variant in ABCB6, c.575G4A, p.(Arg192Gln) (Table 3, Supplementary Figure S3).
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ABCB6 p.Arg192Gln 24281366:91:284
status: NEW104 In our family (Family 10), the unaffected father also carried ABCB6, c.575G4A (p.(Arg192Gln)) in the heterozygous state, indicating that this is a variant with incomplete penetrance and that other factor/s are contributing to the disease phenotype in Patient 10.
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ABCB6 p.Arg192Gln 24281366:104:82
status: NEW113 CYP1B1 can contribute to retinoic acid synthesis in embryonic development,35 and retinoic Table 3 Other variants lacking appropriate segregation-allele frequencies in public databases, conservation and prediction categories Sample (family, pedigree ID) Gene Nucleotide altera- tiona (all heterozygous) Protein alteration Allele frequencies in public databases Consb Prediction tools (SIFT, Polyphen-2, MutTaster) Segregation Congenital cataracts and microcornea/microphthalmia Patient 3 (Family 3, II.1) CRYBA1 c.475G4A p.(Gly159Ser) ESP5400: 0.00316; 1000G: 0.0009 C T,T,D Heterozygous in unaffected mother Coloboma and microphthalmia Patient 9 (Family 9, II.1) CYP1B1 c.868dup p.(Arg290Profs*37) Nil Frameshift Not present in more mildly affected brother, heterozygous in unaffected mother CYP1B1 c.241T4A p.(Tyr81Asn) ESP5400: 0.00327; 1000G: 0.0032 C D,D,D Heterozygous in affected brother and unaffected father BFSP1 c.1620_1621del p.(*541Lysext*7) ESP5400: N/A; 1000G: 0.0014 Frameshift Heterozygous in affected brother and unaffected mother Patient 10 (Family 10, II.1) ABCB6 c.575G4A p.(Arg192Gln) ESP5400: 0.002975; 1000G: 0.0014 NC D,D,D Heterozygous in unaffected father SLC16A12 c.472T4C p.(Ser158Pro) ESP5400: 0.000651; 1000G: Nil C T,T,D Heterozygous in unaffected mother Patient 11 (Family 11, II.1) GDF3 c.974C4T p.(Pro325Leu) Nil C D,D,D Heterozygous in unaffected father CYP1B1 c.1103G4A p.(Arg368His) ESP5400: 0.001496; 1000G: 0.0009 C D,D,D Heterozygous in unaffected mother CYP1B1 c.685G4A p.(Glu229Lys) ESP5400: 0.003817; 1000G: 0.0027 C D,D,T Heterozygous in unaffected father BFSP1 c.401G4C p.(Cys134Ser) Nil C T,D,T Heterozygous in both parents Abbreviations: D, damaging; T, tolerated. aReference sequences used: CYP1B1, NM_000104.3; PAX6, NM_000280.4; CRYBA1, NM_005208.4; BFSP1, NM_001161705.1; ABCB6, NM_005689.2; SLC16A12, NM_213606.3; and GDF3, NM_020634.1.
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ABCB6 p.Arg192Gln 24281366:113:1095
status: NEW