ABCMdb

ABCC8 p.Ser165Leu

Predicted by SNAP2:	A: N (87%), C: N (82%), D: N (93%), E: N (93%), F: N (82%), G: N (93%), H: N (97%), I: N (82%), K: N (93%), L: N (82%), M: N (82%), N: N (97%), P: N (93%), Q: N (97%), R: N (93%), T: N (97%), V: N (87%), W: D (53%), Y: N (61%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, T: N, V: D, W: D, Y: D,

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Publications
[hide] ABCC8 R1420H Loss-of-Function Variant in a Southwe... Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5. Baier LJ, Muller YL, Remedi MS, Traurig M, Piaggi P, Wiessner G, Huang K, Stacy A, Kobes S, Krakoff J, Bennett PH, Nelson RG, Knowler WC, Hanson RL, Nichols CG, Bogardus C
ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.
Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5., [PMID:26246406]

Abstract [show]
Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the beta-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

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Sentences [show]
No. Sentence Comment
70 The other 6 missense variants (all in ABCC8: K1565E, R1420H, G1316Q, M801I, D691E, and S165L) are novel with mAFs of #0.03. Login to comment
102 Although the S165L variant also had a weak association with type 2 diabetes (OR 1.59 [95% CI 1.07-2.35], P = 0.02) (Table 2), conditional analysis showed that the signals from R1420H and S165L are likely to be independent (R1420H: conditional OR 2.04 [1.45-2.86], P = 3.7 3 1025 ; S165L: conditional OR 1.56 [1.05-2.04], P = 0.03). Login to comment
120 The R1420H variant also does not appear to occur at a detectable frequency in Table 2-Association of KCNJ11 and ABCC8 variants with type 2 diabetes, birth weight, and adult maximum BMI in American Indians from the Gila River Indian Community Diabetes (N = 7,710) Birth Weight (N = 2,377) Adult BMI* (N = 5,918) Gene Variant Freqߤ OR (95% CI) minor allele Pߥ B minor allele (g) P&#a7; B minor allele (log e ) P|| KCNJ11 rs5215 V337I 0.39 1.03 (0.94-1.12) 0.54 221.2 0.16 20.0001 0.98 KCNJ11 rs5219 E23K 0.39 1.04 (0.95-1.13) 0.43 218.4 0.22 0.002 0.72 ABCC8 chr11:17414594T.C K1565E 0.01 0.88 (0.56-1.36) 0.56 44.9 0.52 20.051 0.01 ABCC8 chr11:17417205C.T R1420H 0.017 2.02 (1.45-2.82) 3.6 3 10 25 169.1 1.5 3 10 23 20.049 2.5 3 10 23 ABCC8 rs757110 A1369S 0.38 1.03 (0.94-1.12) 0.56 215.5 0.35 0.002 0.60 ABCC8 chr11:17418781C.T G1316Q&#b6; 0.0001 1.04 (0.32-3.38) 0.94 - - 0.037 0.40 ABCC8 chr11:17435016G.T M801I 0.03 1.29 (0.98-1.71) 0.07 272.9 0.08 0.009 0.53 ABCC8 chr11:17449457T.A D691E&#b6; 0.001 0.42 (0.07-2.70) 0.36 - - 20.162 4.1 3 10 23 ABCC8 chr11:17485070G.A S165L 0.01 1.59 (1.07-2.35) 0.02 71.0 0.32 0.078 1.8 3 10 24 OR (95% CI) per copy of the minor allele. Login to comment