ABCC8 p.Val601Ile
| Predicted by SNAP2: | A: D (53%), C: D (63%), D: D (85%), E: D (80%), F: D (75%), G: D (80%), H: D (80%), I: N (78%), K: D (85%), L: D (75%), M: D (53%), N: D (80%), P: D (85%), Q: D (80%), R: D (85%), S: D (63%), T: N (61%), W: D (85%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D, |
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[hide] Clinical and histological heterogeneity of congeni... Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8. Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S, Hussain K
Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8., [PMID:25201519]
Abstract [show]
CONTEXT: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
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74 Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome ABCC8 1 40, 3150 Male 52 2.4 4.3 L1431F/N (c.4291COT/N) Yes - On Dzx at 6.4 years 2 40, 4000 Male 2 2.4 1.9 p.?/N (c.2697C4AOT/N) Yes - Off Dzx at 2 years 3 40, 5010 Female !1 2.6 8.6 E1507K/N (c.4519GOA/N) Yes - On Dzx at 2.3 years 4 40, 5600 Male !1 2.0 7.5 A1508P/N (c.4522GOC/N) Yes - On Dzx at 12 years 5 37, 4820 Male !1 2.0 9.0 A1153T/N (c.3457GOA/N) Yes - On Dzx at 4 years 6 38, 3630 Female 72 3.1 !2 A1153T/N (c.3457GOA/N) Yes - On Dzx at 2 years 8 35, 2820 Male !1 1.2 12.9 A1185V/N (c.3554COT/N) Yes - Off Dzx at 8 months 9 36, 4450 Male !1 2 28.5 p.?/N (c.3992-9GOA/N) Yes - Off Dzx after 4.5 months 10 41, 2780 Female !1 1 9.3 D1472N/N (c.4414GOA/N) Yes - Off Dzx after 10 months 11 38, 3750 Male !1 2.6 5.90 V601I/N (c.1801GOA/N) Yes - Off Dzx after 14 months 13 40, 4160 Female !1 2.4 14.8 V185fs/N (c.554delT/N) No Diffuse Off octreotide at 5 years 14 37, 3090 Male !1 0.6 12.4 p.?/N (c.3992-9GOA/N) No Focal On octreotide at 9.5 years 15 40, 3600 Male !1 2.7 6.7 H627fs/N (c.1879delC/N) No Diffuse Off octreotide at 18 months 16 40, 4700 Female !1 2.0 !2 E1507K/N (c.4519GOA/N) NA - No treatment required 17 40, 4200 Male !1 1.0 !2 D1031N/N (c.3091GOA/N) NA - No treatment required 18 41, 4850 Male !1 1.2 10.1 M1V/N (c.1AOG/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 19 38, 2400 Male !1 2.1 16.3 D1194V; R1437Q/N (c.3581AOT; c.4310GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 20 40, 4580 Female !1 1.1 103 A1493T/N (c.4477GOA/N) Yes a No Diffuse Near-total pancreatectomy (95%) 21 40, 4600 Male !1 1.2 22.5 K890fs/N (c.2669_2675del/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 22 40, 4335 Male !1 2.6 3.4 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 23 40, 3030 Male !1 1.8 15.6 p.?/N (c.3992-9GOA/N) Yes No Focal Partial pancreatectomy 24 40, 2770 Male !1 2.2 3.4 p.?/N (c.580-1GOC/N) No Indeterminate (PVS) Partial pancreatectomy - focal lesion on histology 25 41, 4290 Male 2 2.3 4.32 E128K/N (c.382GOA/N) No Focal Hypoglycaemia resolved after removal of focal lesion 27 40, 5095 Male !1 2.0 10.5 L1171X/N (c.3512delT/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 29 37, 3560 Male !1 1.6 21.8 p.?/N (c.1629-2AOC/N) No Focal Hypoglycaemia resolved after removal of focal lesion 30 40, 2750 Male !1 1.5 16.4 G111R/N (c.331GOA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 31 37, 3340 Male !1 2.1 15 H627fs/N (c.1879delC/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 32 41, 4950 Male !1 1.2 11.95 R934X/N (c.2800COT/N) No Focal Hypoglycaemia resolved after removal of focal lesion 33 40, 3080 Female 12 1.5 4.6 S12X/N (c.35COA/N) Yes No Focal Hypoglycaemia resolved after removal of focal lesion 34 39, 3600 Male !1 2.5 8 R1494W/N (c.4480COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 37 36, 3410 Male !1 0.9 17.42 R1494W/N (c.4480COT/N) No Focal Partial pancreatectomy Table 1 Continued Patient ID GA (weeks), birth weight (g) Gender Age at presentation (weeks) Blood glucose (mmol/l) Serum insulin (mU/l) Mutation protein description (DNA description) LOH Dzx Resp PET CT/PVS Outcome 38 39, 4900 Female !1 1.4 23.61 A113V/N (c.338COT/N) No Diffuse (PVS) Near-total pancreatectomy (95%) 39 36, 3210 Male !1 0.6 114 Mosaic Q54X (c.160COT) No Diffuse Near-total pancreatectomy (95%) 40 41, 4300 Female !1 2.1 17 Q954X/N (c.2860COT/N) No Diffuse Near-total pancreatectomy (95%) 41 36, 2730 Male !1 ?
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ABCC8 p.Val601Ile 25201519:74:921
status: NEW114 (c.3992-9GOA) No Not available Not available Disease causing (5)a D1472N (c.4414GOA) Yes Deleterious Damaging Disease causing (24)a V601I (c.1801GOA) No Neutral Tolerated Disease causing Novela V185fs (c.554delT) Yes Not available Not available Disease causing Novel H627fs (c.1879delC) No Not available Not available Disease causing (9)a D1031N (c.3091GOA) No Neutral Tolerated Disease causing Novel M1V (c.1AOG) No Neutral Damaging Disease causing (6)a A1493T (c.4477GOA) Yes Deleterious Damaging Disease causing (14)a R1494W (c.4480COT) Yes Deleterious Damaging Disease causing (25)a KCNJ11 M209I (c.627GOA) No Neutral Damaging Disease causing Novel R54H (c.161GOA) No Deleterious Damaging Disease causing Novela E292K (c.874GOA) No Deleterious Damaging Disease causing Novel T62M (c.185COT) No Deleterious Damaging Disease causing (4) R177W (c.529AOT) No Deleterious Damaging Disease causing Novel a These patients were included in reference (3).
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ABCC8 p.Val601Ile 25201519:114:132
status: NEW