rs1064794268

chr7-44153396-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.113A>C(p.Gln38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q38L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 1.47

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44153396-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2691828.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 7-44153396-T-G is Pathogenic according to our data. Variant chr7-44153396-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 420070.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.113A>C	p.Gln38Pro	missense_variant	2/10	ENST00000403799.8
GCK	NM_033507.3	c.116A>C	p.Gln39Pro	missense_variant	2/10
GCK	NM_033508.3	c.110A>C	p.Gln37Pro	missense_variant	3/11
GCK	NM_001354800.1	c.113A>C	p.Gln38Pro	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.113A>C	p.Gln38Pro	missense_variant	2/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Mar 19, 2024	The c.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 1508276, 11079754, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors). In summary, c.113A>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2021	Variant summary: GCK c.113A>C (p.Gln38Pro) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.113A>C has been reported in the literature in individuals affected with Monogenic Diabetes including in a pair of siblings as well as a reported de novo occurrence (Prisco_2000, Massa_2001, Velho_2004, Aloi_2017, Bitterman_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different amino acid change affecting the same codon (p.Gln38Leu) has been reported in association with monogenic diabetes (HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2017	The Q38P variant has been published previously in association with MODY, including an apparently de novo occurrence (Prisco et al., 2000; Massa et al., 2001; Osbak et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q38P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (Q38L) and in nearby residues (V33A, R36W/Q, M37R, E40K, M41T, R43S/G/C/P/H) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 38 of the GCK protein (p.Gln38Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (MODY) (PMID: 11079754, 11508276, 28726111, 36227502). ClinVar contains an entry for this variant (Variation ID: 420070). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Maturity-onset diabetes of the young type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Translational Genomics Laboratory, University of Maryland School of Medicine

Jun 07, 2017

The c.113A>C variant in codon 38 (exon 2) of the glucokinase gene, GCK, results in the substitution of Glutamine to Proline. The c.113A>C variant was previously identified in the patient's nephew, who has a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY). It was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in two patients with a MODY2 phenotype (11508276;11079754). Another variant at this codon, Gln38Leu, has been found to co-segregate with fasting hyperglycemia in a different family (K. Colclough, personal communication, April 10, 2017). Additionally, multiple lines of computational evidence (SIFT, LRT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD, GERP, PROVEAN) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4-mod, PM2, PP1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.99	D;D;D;P;.
Vest4		0.94
MutPred		0.84		.;Gain of glycosylation at Q38 (P = 0.0262);.;.;Gain of glycosylation at Q38 (P = 0.0262);
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064794268; hg19: chr7-44192995;