Table 1.
Genetic study results of 154 patients/families with suspected Cbl malabsorption
| Identifiera | DNA mutationb | Genotypec | predicted consequence mRNA or protein leveld | Interpretation |
|---|---|---|---|---|
| DT |
CUBN c.250C>T |
hom |
p.Gln84* |
IGS |
| MGA47 |
CUBN c.252+1G>A & del ~90 kb proximal of 5'-end to Intron 28 |
hom |
splice site mutation & partial gene deletion |
IGS |
| Fam SA |
CUBN c.434G>A |
hom |
p.Gly145Gln |
IGS |
| ZX-1 |
CUBN c.434G>A |
hom |
p.Gly145Gln |
IGS |
| MGA57 |
CUBN c.489G>A & c.1530G>A |
comp het |
c.489_490ins137bp; p.Gly164fs & Exon 13 skipping; p.Val473fs |
IGS |
| Norge 1 |
CUBN c.673T>A |
hom |
p.Cys225Ser |
IGS |
| MGA53 |
CUBN c.889C>T & c.1010C>T |
comp het |
p.Gln297* & p.Pro337Leu |
IGS |
| MGA1 |
CUBN c.1010C>T & c.2673C>A |
comp het |
p.Pro337Leu & p.Cys891* |
IGS |
| MGA20 |
CUBN c.1010C>T & del >150 kb proximal of 5'-end to ~150 kb distal of 3'-end |
comp het |
p.Pro337Leu & complete gene deletion |
IGS |
| MGA29 |
CUBN c.1436C>G & del >150 kb proximal of 5'-end to >160 kb distal of 3'-end |
comp het |
p.Leu479* & complete deletion |
IGS |
| HS98 |
CUBN c.1526delG & c.1865delC |
comp het |
p.Gly509fs & p.Thr621fs |
IGS |
| MGA34 |
CUBN c.1838delG & c.3890C>T |
comp het |
p.Gly613fs & p.Pro1297Leu |
IGS |
| KT |
CUBN c.1951C>T |
hom |
p.Arg651* |
IGS |
| Taiwan 1 |
CUBN c.1951C>G & ? |
comp het |
p.Arg651Gly (rs182512508) & ? |
IGS |
| MGA11 |
CUBN c.2068A>G & c.3330-439C>G |
comp het |
p.Ile690Val & aberrant splicing |
IGS |
| MGA66 |
CUBN c.2486C>T & ? |
comp het |
p.Ser829Leu & ? |
IGS |
| MGA76 |
CUBN c.2511_2529del19bp & c.4168G>A |
comp het |
p.Pro837fs & p.Gly1390Ser |
IGS |
| MGA3 |
CUBN c.2594G>A |
hom |
p.Ser865Asn |
IGS |
| MGA43 |
CUBN c.2594G>A & ? |
comp het |
p.Ser865Asn & ? |
IGS |
| MT2 |
CUBN c.2594G>A & c.3749C>T |
comp het |
p.Ser865Asn & p.Ser1250Phe |
IGS |
| 4655-2590 |
CUBN c.2614_2615delGA |
hom |
p.Asp872fs |
IGS |
| MGA78 |
CUBN c.2614_2615delGA |
hom |
p.Asp872fs |
IGS |
| MGA56 |
CUBN c.2949C>A |
hom |
p.Tyr983* |
IGS |
| MGA14 |
CUBN c.3056C>G |
hom |
p.Ser1019* |
IGS |
| MGA26 |
CUBN c.3096delT & ? |
comp het |
p.Thr1032* & ? |
IGS |
| MGA7 |
CUBN c.3300-439C>G |
hom |
aberrant splicing |
IGS |
| RL02 |
CUBN c.3577T>G |
hom |
p.Trp1193Gly |
IGS |
| FM1(20 cases) |
CUBN c.3890C>T |
hom |
p.Pro1297Leu |
IGS |
| AT01 |
CUBN c.3890C>T |
hom |
p.Pro1297Leu |
IGS |
| MGA17 |
CUBN c.3890C>T |
hom |
p.Pro1297Leu |
IGS |
| MGA72 |
CUBN c.3890C>T |
hom |
p.Pro1297Leu |
IGS |
| MGA65 |
CUBN c.3999C>A & ? |
comp het |
p.Cys1333* & ? |
IGS |
| KA95 |
CUBN c.4115C>G |
hom |
p.Thr1372Arg |
IGS |
| MGA2 |
CUBN c.4115C>G |
hom |
p.Thr1372Arg |
IGS |
| Fam A |
AMN c.14delG |
hom |
p.Gly5fs |
IGS |
| Fam C |
AMN c.14delG |
hom |
p.Gly5fs |
IGS |
| Fam D |
AMN c.14delG |
hom |
p.Gly5fs |
IGS |
| Norge 2 |
AMN c.14delG |
hom |
p.Gly5fs |
IGS |
| MGA12 |
AMN c.43+1G>T & c.701G>T |
comp het |
splice site mutation & p.Cys234Phe |
IGS |
| MGA88 |
AMN c.43+4A>G & c.100delG |
comp het |
splice site mutation & p.Ala34fs |
IGS |
| MGA5 |
AMN c.44-3C>G |
hom |
splice site mutation |
IGS |
| Fam K |
AMN c.122C>T |
hom |
p.Thr41Ile |
IGS |
| MGA51 |
AMN c.122C>T & c.1118_1119insCGCT |
comp het |
p.Thr41Ile & p.Leu374fs |
IGS |
| MGA77 |
AMN c.176T>C |
hom |
p.Leu59Pro |
IGS |
| FT |
AMN c.208-1G>C |
hom |
splice site mutation |
IGS |
| Fam M |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| CT |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| ET |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MT |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| Jor 8.7 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| Jor 7.7 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| Fam C89 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| Israel I |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| Israel II |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA30 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA45 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA52 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA58 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA59 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA69 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA75 |
AMN c.208-2A>G |
hom |
Exon 4 skipping |
IGS |
| MGA22 |
AMN c.295delG |
hom |
p.Gly98fs |
IGS |
| MGA37 |
AMN c.468_469insT & c.1006+34_48del15bp |
comp het |
p.Gly157fs & Exon 9 skipping |
IGS |
| BT |
AMN c.514-34G>A |
hom |
new splice site leading to c.513_514ins32bp; p.Thr172fs |
IGS |
| MGA83 |
AMN c.663G>A |
hom |
p.Trp221* |
IGS |
| Fam AK |
AMN c.683_730del48bp |
hom |
p.Gln228_Leu243del |
IGS |
| PT |
AMN c.761G>A |
hom |
p.Gly254Glu |
IGS |
| MGA19 |
AMN c.967_(1169+15)del296bp & c.977_978insCCCG |
comp het |
partial gene deletion & p.Arg326fs |
IGS |
| MGA86 |
AMN c.1006+16_30del15bp |
hom |
unknown |
IGS |
| Sudan 1 |
AMN c.1006+34_48del15bp |
hom |
Exon 9 skipping |
IGS |
| MGA8 |
AMN c.1006+34_48del15bp |
hom |
Exon 9 skipping |
IGS |
| MGA82 |
AMN c.1006+34_48del15bp |
hom |
Exon 9 skipping |
IGS |
| MGA13 |
AMN c.1006+34_48del15bp & c.1314_1315delCA |
comp het |
Exon 9 skipping & p.His438fs |
IGS |
| Belgium 1 |
AMN c.1006+36_50del15bp & c.1253_1254insA |
comp het |
unknown & p.Leu419fs |
IGS |
| MGA38 |
AMN c.1014_1021delCCTCGGCG |
hom |
p.Leu339fs |
IGS |
| MGA73 |
AMN c.1014_1021delCCTCGGCG |
hom |
p.Leu339fs |
IGS |
| MGA81 |
AMN c.1170-6C>T & ? |
comp het |
splice site mutation? & ? |
IGS? |
| MGA74 |
AMN c.1257+10C>T |
hom |
splicing defect? |
IGS |
| MGA68 |
AMN c.1314_1315delCA |
hom |
p.His438fs |
IGS |
| France 1 |
GIF c.79+1G>A |
hom |
splice site mutation |
IFD |
| MGA4 |
GIF c.79+1G>A |
hom |
splice site mutation |
IFD |
| MGA25 |
GIF c.79+1G>A |
hom |
splice site mutation |
IFD |
| MGA49 |
GIF c.79+1G>A & del Intron 8 to distal of 3'-end |
comp het |
splice site mutation & partial gene deletion |
IFD |
| MGA79 |
GIF c.79+1G>A & c.137C>T |
comp het |
splice site mutation & p.Ser46Leu |
IFD |
| MGA67 |
GIF c.79+1G>A & c.290T>C |
comp het |
splice site mutation & p.Met97Thr |
IFD |
| MGA64 |
GIF c.79+1G>A & c.673A>C |
comp het |
splice site mutation & p.Ser225Arg |
IFD |
| Kuwait 1 |
GIF c.80-1G>A |
hom |
splice site mutation |
IFD |
| Kuwait 2 |
GIF c.80-1G>A |
hom |
splice site mutation |
IFD |
| IT |
GIF c.137C>T |
hom |
p.Ser46Leu |
IFD |
| NT |
GIF c.137C>T |
hom |
p.Ser46Leu |
IFD |
| LT |
GIF c.161delA |
hom |
p.Asn54fs |
IFD |
| Fam 8 |
GIF c.183_186delGAAT |
hom |
p.Met61fs |
IFD |
| MGA33 |
GIF c.183_186delGAAT |
hom |
p.Met61fs |
IFD |
| MGA55 |
GIF c.183_186delGAAT |
hom |
p.Met61fs |
IFD |
| MGA39 |
GIF c.183_186delGAAT & c.659T>C |
comp het |
p.Met61fs & p.Ile220Thr |
IFD |
| MGA27 |
GIF c.256+2T>G & c.659T>C |
comp het |
splice site mutation & p.Ile220Thr |
IFD |
| MGA35 |
GIF c.290T>C & ? |
comp het |
p.Met97Thr & ? |
IFD |
| MGA54 |
GIF c.431_438delAGAAGAAC & c.974_975insG |
comp het |
p.Gln144fs & p.Val325fs |
IFD |
| MGA48 |
GIF c.469T>C & ? |
comp het? |
p.Phe157Leu & ? |
IFD? |
| HT |
GIF c.685G>A |
hom |
p.Ala229Thr |
IFD |
| MGA36 |
GIF c.685G>A |
hom |
p.Ala229Thr |
IFD |
| D2914 |
GIF c.938C>T & ? |
comp het |
p.Thr313Ile & ? |
IFD |
| MGA24 |
GIF c.1073+5G>A |
hom |
splice site mutation |
IFD |
| MGA63 |
GIF c.1073+5G>A |
hom |
splice site mutation |
IFD |
| MGA92 |
GIF c.1073+5G>A |
hom |
splice site mutation |
IFD |
| AT |
GIF c.1175_1176insT |
hom |
p.Thr393fs |
IFD |
| MGA61 |
GIF c.1222G>A |
hom |
p.Glu408Lys |
IFD |
| MGA9 |
LMBRD1 c.404delC & c.1056delG |
comp het |
p.Thr135fs & p.Leu352fs |
cblF defect |
| JCA1 |
AMN/CUBN excluded; GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA6 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1/TCN2 screened |
n/a |
n/a |
differential diagnosis? |
| MGA10 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA15 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA16 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA18 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA21 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA23 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1/TCN2 screened |
n/a |
n/a |
differential diagnosis? |
| MGA28 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA31 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA32 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA40 |
AMN/CUBN/GIF excluded; FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA41 |
AMN/CUBN/GIF excluded; FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA42 |
AMN/CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA44 |
AMN/CUBN/GIF/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA46 |
CUBN/GIF excluded; AMN/FUT2/CD320/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA50 |
AMN/CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA62 |
AMN/CUBN/GIF/FUT2/CD320/ABCC1/LMBRD1/TCN1/TCN2 screened |
n/a |
n/a |
TCN1 defect? |
| MGA70 |
AMN/CUBN/GIF/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA71 |
AMN/CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA80 |
AMN/CUBN/GIF/ABCC1/LMBRD1 screened |
n/a |
n/a |
differential diagnosis? |
| MGA84 |
AMN/CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA85 |
AMN excluded; CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA87 |
AMN/CUBN/GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA89 |
GIF excluded; AMN/CUBN screened |
n/a |
n/a |
differential diagnosis? |
| MGA90 |
AMN/CUBN excluded; GIF screened |
n/a |
n/a |
differential diagnosis? |
| MGA91 | TCN1 c.747+3A>C & ?; GIF screened | comp het? | splice site mutation? | TCN1 defect? |
aCases are ordered by the location of the mutations in the three genes CUBN, AMN, and GIF, followed by potential differential diagnoses by case code. Additional file 1 online contains a sortable Excel table with additional information.
bNumbering relative to adenine in the first ATG start codon of CUBN (GenBank RefSeq: NM001081.2), AMN (GenBank RefSeq: NM030943.1), and GIF (GenBank accession NM005142.2).
chom means homozygous, comp het means compound heterozygous, n/a means not applicable.
dNumbering relative to the first methionine deduced from the cDNA sequences. Mutations which seemingly caused a frameshift were described as to where the frameshift occurred rather than when the next stop codon was predicted. Where available experimentally confirmed splicing defects on the mRNA level are listed (for details see text).