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Table 1 Genetic study results of 154 patients/families with suspected Cbl malabsorption

From: Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns

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?

  1. 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.
  2. 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).
  3. chom means homozygous, comp het means compound heterozygous, n/a means not applicable.
  4. 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).