Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age

Table 2

Missense variants and exon deletion of MODY genes in Japanese probands.

Gene

Protein variant^a

Location

Nucleotide changes

Carrier frequency

Clinical information

Possible functional impact

Conservation (protein)

Class

Patients

Controls ()

Refs.

HGMD professional

Protein level

RNA level

Polyphen-2/SIFT

Splice

ESE/ESS

GCK

M41T

Exon 2

c.122 T>C

1

0

[16]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

T60I

Exon 2

c.179 C>T

1

NA

[17]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

G72R

Exon 3

c.214 G>A

1

NA

[18]

DM

Possibly damaging/deleterious

Yes

No/possible

Yes

Pathogenic

L77P

Exon 3

c.230 T>C

1

NA

[19]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

G81C

Exon 3

c.241 G>T

1

0

[20]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

G147D

Exon 4

c.440 G>A

1

0

Unknown

—

Possibly damaging/deleterious

No

No/no

—

Unknown significant

T206M

Exon 6

c.617 C>T

1

NA

[21]

DM

Possibly damaging/deleterious

No

No/possible

Yes

Pathogenic

G223S

Exon 6

c.667 G>A

2

0

[21–22]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

T228M

Exon 7

c.683 C>T

4

0

[23]

DM

Possibly damaging/deleterious

No

Possible/possible

Yes

Pathogenic

Q239R

Exon 7

c.716 A>G

1

0

[24]

DM

Benign/tolerated

No

Possible/no

No

Likely pathogenic

N254D

Exon 7

c.760 A>G

1

0

Unknown

—

Possibly damaging/deleterious

No

Possible/no

—

Unknown significant

L324P

Exon 8

c.971 T>C

1

NA

[25]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Likely pathogenic

S336X

Exon 8

c.1,007 C>A

1

0

[16–20]

DM

Possibly damaging/deleterious

No

Possible/possible

—

Pathogenic

R377H

Exon 9

c.1,130 G>A

1

0

[19]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Likely pathogenic

R377S

Exon 9

c.1,129 C>A

2

NA

[16]

DM

Possibly damaging/deleterious

Yes

No/possible

Yes

Pathogenic

S383L

Exon 9

c.1,148 C>T

1

NA

[26]

DM

Possibly damaging/deleterious

No

No/possible

No

Pathogenic

R392C

Exon 9

c.1,174 C>T

1

0

[27]

DM

Possibly damaging/deleterious

No

Possible/possible

No

Likely pathogenic

A454V

Exon 10

c.1,361 C>T

1

NA

[27]

DM

Possibly damaging/deleterious

Yes

No/possible

Yes

Pathogenic

E5-6 deletion

Exon 5-6

—

1

NA

[16]

DM

—

—

—

—

Pathogenic

HNF4α

V251G

Exon 7

c.752 T>G

1

0

Unknown

—

Possibly damaging/deleterious

Yes

Possible/no

—

Unknown significant

HNF1α

A116V

Exon 2

c.347 C>T

1

NA

[24]

DM

Possibly damaging/deleterious

Yes

Possible/possible

Yes

Pathogenic

R131W

Exon 2

c.391 C>T

1

0

[28]

DM

Possibly damaging/deleterious

Yes

No/possible

Yes

Pathogenic

R271W

Exon 4

c.811 C>T

1

NA

[29]

DM

Possibly damaging/deleterious

No

Possible/no

Yes

Pathogenic

HNF1β

Whole gene deletion

—

1

NA

[30]

DM

—

—

—

—

Pathogenic

Amino acid numbers and nucleotide changes are based on NCBI RefSeq NM_175914.3 and NP_787110.2 for HNF4α, NM_000162.3 and NP_000153.1 for GCK, and NM_000545.5 and NP_000536.5 for HNF1α. ^aBold font denotes novel missense mutations in diabetes-specific missense mutations. All changes were heterozygous. NA: not analyzed. Possible functional effects of identified variants, especially unknown (novel) variants, were identified with two web-based programs, PolyPhen 2 (http://genetics.bwh.harvard.edu/pph2/) and SIFT (http://sift.bii.a-star.edu.sg/www/SIFT_seq_submit2.html). Potential effects on splicing were evaluated with HSF (Human Splicing Finder; http://www.umd.be/HSF3/technicaltips.html). Clinical information was evaluated with HGMD professional (http://www.hgmd.cf.ac.uk/) and ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/). Sequence conservation was evaluated with HGMD professional (http://www.hgmd.cf.ac.uk/).