rs193922317

chr7-44149778-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000162.5(GCK):c.661G>A(p.Glu221Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,780 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.91

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 7-44149778-C-T is Pathogenic according to our data. Variant chr7-44149778-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36241.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-44149778-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.661G>A	p.Glu221Lys	missense_variant	6/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.309C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.661G>A	p.Glu221Lys	missense_variant	6/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461780 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2023	Variant summary: GCK c.661G>A (p.Glu221Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251548 control chromosomes (gnomAD, Guazzini_1998). c.661G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (Guazzini_1998, Mantovani_2003, Caetano_2012, Wang_2019), and has been observed segregating with disease within families (Guazzini_1998, Caetano_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. Wang_2019 found that the relative activity level of the variant protein was 47%. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Feb 28, 2024	The c.661A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 221 (p.(Glu221Lys)) 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 0.789, 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 is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP. This variant was identified in 4 unelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMID: 23295292, internal lab contributors). This variant has been identified in 25 unrelated individuals with hyperglycemia and segregated with the phenotype, with 17 informative meioses in at least 7 families (PS4, PP1_Strong; PMIDs: 10694920, 12955723, 31658956, 34462253, 35592779, 35733065, 23295292, and 30592380). A relative activity index (RAI) was calculated for this variant but the wild type parameters are outside of MDEP's recommendations; therefore, this data cannot be used towards PS3 (PMID: 30592380). In summary, c.661A>G 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, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 221 of the GCK protein (p.Glu221Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 23295292, 26226118, 31216263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36241). 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%. Experimental studies have shown that this missense change affects GCK function (PMID: 30592380). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PM2, PP1_Strong, PS4, PP4_Moderate, PP2, PS3 -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2017

The p.E221K pathogenic mutation (also known as c.661G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 661. The glutamic acid at codon 221 is replaced by lysine, an amino acid with similar properties. This mutation has been described in multiple individuals of Italian descent with impaired glucose tolerance or maturity-onset diabetes of the young (MODY) (Guazzini B et al. Hum. Mutat., 1998;12:136; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Mantovani V et al. Hum. Mutat., 2003 Oct;22:338). Furthermore, in a Brazilian family with MODY, this mutation co-segregated with hyperglycemia and was absent in normoglycemic family members (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.94
MutPred		0.83		.;Gain of methylation at E221 (P = 0.0028);.;.;.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.87
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922317; hg19: chr7-44189377; COSMIC: COSV60786559; COSMIC: COSV60786559;