Table 2.
RET coding and splice-site variants in patients with Hirschsprung’s disease
| DNA change1 | Protein change | Number of affected subjects2 | Variant type | Exon/ intron | Location on chromosome 103 | PolyPhen-2 Prediction4 | SIFT prediction4 |
|---|---|---|---|---|---|---|---|
| c.166C>A | p.L56M | 1 | missense | exon 2 | 43595999 | benign | tolerated |
| c.286T>G | p.Y96D | 1 | missense | exon 2 | 43596119 | probably damaging | affect protein function |
| c.418C>T5 | p.P140S | 1 | missense | exon 3 | 43597870 | possibly damaging | tolerated |
| c.436T>C | p.Y146H | 1 | missense | exon 3 | 43597888 | benign | tolerated |
| c.523C>T5 | p.R175C | 1 | missense | exon 3 | 43597975 | probably damaging | affect protein function |
| c.628G>A5 | p.E210K | 1 | missense | exon 4 | 43600402 | benign | tolerated |
| c.898G>A5 | p.D300N | 1 | missense | exon 5 | 43601854 | probably damaging | affect protein function |
| c.1157C>T | p.A386V | 1 | missense | exon 6 | 43604572 | benign | tolerated |
| c.1187C>T5 | p.S396L | 1 | missense | exon 6 | 43604602 | benign | affect protein function |
| c.1193T>C5 | p.L398P | 1 | missense | exon 6 | 43604608 | probably damaging | affect protein function |
| c.1336G>C | p.G446R | 2 | missense | exon 7 | 43606727 | benign | tolerated |
| c.1354C>A | p.L452I | 1 | missense | exon 7 | 43606745 | benign | tolerated |
| c.1387G>A5 | p.G463R | 1 | missense | exon 7 | 43606778 | probably damaging | affect protein function |
| c.1400T>C5 | p.V467A | 1 | missense | exon 7 | 43606791 | probably damaging | affect protein function |
| c.1701C>A5 | p.D567E | 1 | missense | exon 9 | 43608353 | possibly damaging | affect protein function |
| c.1894G>A | p.E632K | 1 | missense | exon 11 | 43609942 | benign | tolerated |
| c.2372A>T | p.Y791F | 2 | missense | exon 13 | 43613908 | possibly damaging | tolerated |
| c.2390A>T5 | p.D797V | 1 | missense | exon 13 | 43613926 | probably damaging | tolerated |
| c.2410G>A | p.V804M | 1 | missense | exon 14 | 43614996 | probably damaging | affect protein function |
| c.2522C>T | p.P841L | 1 | missense | exon 14 | 43615108 | probably damaging | affect protein function |
| c.2550C>G5 | p.D850E | 1 | missense | exon 14 | 43615136 | probably damaging | tolerated |
| c.2590T>C5 | p.Y864H | 1 | missense | exon 14 | 43615176 | probably damaging | affect protein function |
| c.2657G>A | p.R886Q | 1 | missense | exon 15 | 43615578 | probably damaging | affect protein function |
| c.2680G>A | p.G894S | 1 | missense | exon 15 | 43615601 | probably damaging | affect protein function |
| c.2944C>T | p.R982C | 6 | missense | exon 18 | 43620335 | probably damaging | affect protein function |
| c.3142C>G5 | p.L1048V | 1 | missense | exon 19 | 43622125 | probably damaging | tolerated |
| c.3278A>G5 | p.D1093G | 1 | missense | exon 20 | 43623650 | probably damaging | affect protein function |
| c.750_751delCG | p.E251G frameshift X102 | 1 | frameshift | exon 4 | 43600524 - 43600525 | - | - |
| c.1261C>T | p. Q421X | 1 | nonsense | exon 6 | 43604676 | - | - |
| c.1370C>A5 | p.S457X | 1 | nonsense | exon 7 | 43606761 | - | - |
| c.1914delC5 | p.I638M frameshift X37 | 1 | frameshift | exon 11 | 43609962 | - | - |
| c.2943C>G5 | p.Y981X | 1 | nonsense | exon 18 | 43620334 | - | - |
| c.1759+1G>A5 | - | 1 | splice-site disruption | intron 9 | 43608412 | - | - |
| c.1879+1G>A | - | 2 | splice-site disruption | intron 10 | 43609124 | - | - |
Nucleotides numbered with +1 representing the A of the ATG translation initiation codon of the GenBank reference sequence for RET cDNA (NM_020975.4)
Thirty-four cases had one variant each and four cases had two variants each. Among the four cases with two variants each, all variants except for p.I638M frameshiftX37 have been reported previously: one case had p.L452I and p.P841L, another had p.L56M and p.A386V, the third had p.V804M and p.R982C, and the fourth had p.I638M frameshiftX37 and p.R982C.
Based on GenBank human reference sequence for chromosome 10 (NC_000010.10), Genome Reference Consortium Human Build 37 (GRCh37.p5), February 2009
PolyPhen-2 and SIFT used to predict the effect of missense variants on protein function based on sequence comparisons and/or the physical characteristics of amino acids
Previously unreported variant, based on a search for these variants in previous reports and in the Human Gene Mutation Database, the Multiple Endocrine Neoplasia type 2 RET proto-oncogene database, dbSNP, 1000 Genomes (www.1000genomes.org), and the National Heart, Lung, and Blood Institute Exome Sequencing Project database (http://evs.gs.washington.edu/EVS/)