J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website https://www.jofem.org

Short Communication

Volume 12, Number 6, December 2022, pages 188-197

Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

Figure 2. Pedigree and electropherograms of the index patient. (a) Pedigree of the family of the studied patient with GDM. Arrow is the index patient. (b) Electropherograms of the homozygous mutant index patient with c.2843C>T variant. (c) The IRS1 homozygous wild type individual missing the c.2843C>T variant. (d) The homozygous mutant index patient with c.3661C>T variant. (e) IRS1 homozygous wild type individual missing the c.3661C>T variant. Arrow is the position of the variants.

Figure 3. Multiple sequence alignment of human IRS1 protein sequence (NP_005535.1) with its mammalian homologs. Black arrows indicate residue positions Pro948 and Arg1221.

**Table 1.** Description of HNF1A Variants Detected in the Index Patient
RefSNP number	Position in genomic DNA	Position in CDS	Position in protein	Global MAF	ClinVar^d	References
^aMAF of the global population from 1000 Genomes Study. ^bMAF of the global population from gnomAD. ^cThe positions are in the transcript ENST00000400024.6. ^dClinVar interpretation and clinical significance for the phenotype of maturity-onset diabetes of the young type 3. CDS: coding DNA sequence; MAF: minor allele frequency.
rs1169289	Chr12:g.121416622C>G	c.51C>G	p.Leu17=	G = 0.4285^a G = 0.4645^b	Benign	[28]
rs2259820	Chr12:g.121435342C>T	c.1375C>T	p.Leu459=	T = 0.3167^a T = 0.3302^b	Benign	[28, 29]
rs2259816	Chr12:g.121435587G>T	c.1620G>T^c	p.Val540=^c	T = 0.3588^a T = 0.3845^b	Benign	[30, 31]
rs1169288	Chr12:g.121416650A>C	c.79A>C	p.Ile27Leu	C = 0.2985^a C = 0.3479^b	Benign	[32-34]
rs2464196	Chr12:g.121435427G>A	c.1460G>A	p.Ser487Asn	A = 0.3177^a A = 0.3296^b	Benign	[28, 35]
rs2464195	Chr12:g.121435475G>A	c.1508G>A^c	p.Arg503His^c	A = 0.3596^a A = 0.3800^b	Benign	[36]

Table 1. Description of HNF1A Variants Detected in the Index Patient

RefSNP number

Position in genomic DNA

Position in CDS

Position in protein

Global MAF

ClinVar^d

References

^aMAF of the global population from 1000 Genomes Study. ^bMAF of the global population from gnomAD. ^cThe positions are in the transcript ENST00000400024.6. ^dClinVar interpretation and clinical significance for the phenotype of maturity-onset diabetes of the young type 3. CDS: coding DNA sequence; MAF: minor allele frequency.

rs1169289

Chr12:g.121416622C>G

c.51C>G

p.Leu17=

G = 0.4285^a
G = 0.4645^b

Benign

[28]

rs2259820

Chr12:g.121435342C>T

c.1375C>T

p.Leu459=

T = 0.3167^a
T = 0.3302^b

Benign

[28, 29]

rs2259816

Chr12:g.121435587G>T

c.1620G>T^c

p.Val540=^c

T = 0.3588^a
T = 0.3845^b

Benign

[30, 31]

rs1169288

Chr12:g.121416650A>C

c.79A>C

p.Ile27Leu

C = 0.2985^a
C = 0.3479^b

Benign

[32-34]

rs2464196

Chr12:g.121435427G>A

c.1460G>A

p.Ser487Asn

A = 0.3177^a
A = 0.3296^b

Benign

[28, 35]

rs2464195

Chr12:g.121435475G>A

c.1508G>A^c

p.Arg503His^c

A = 0.3596^a
A = 0.3800^b

Benign

[36]

**Table 2.** The Co-Occurrence of the Two Variants p.Pro948Leu (rs370373307) and p.Arg1221Cys (rs754239320) in the Same Haplotype
	rs370373307 G>A MAF = 0.00007569
The estimated probability that these two variants occur together among the same individual is equal to 0%. Adapted from gnomAD v2.1.1. MAF: minor allele frequency.
rs754239320 4G>A MAF = 0.00005627	G	248,813	19
A	14	0

Table 2. The Co-Occurrence of the Two Variants p.Pro948Leu (rs370373307) and p.Arg1221Cys (rs754239320) in the Same Haplotype

rs370373307 G>A
MAF = 0.00007569

The estimated probability that these two variants occur together among the same individual is equal to 0%. Adapted from gnomAD v2.1.1. MAF: minor allele frequency.

rs754239320 4G>A
MAF = 0.00005627

248,813