rs193922297

chr7-44150990-A-Gchr7-44150990-A-T

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.449T>C(p.Phe150Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. F150L) 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
• Conservation: PhyloP100: 9.25

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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr7-44150989-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3068510.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 7-44150990-A-G is Pathogenic according to our data. Variant chr7-44150990-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 36218.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.449T>C	p.Phe150Ser	missense_variant	4/10	ENST00000403799.8
GCK	NM_033507.3	c.452T>C	p.Phe151Ser	missense_variant	4/10
GCK	NM_033508.3	c.446T>C	p.Phe149Ser	missense_variant	5/11
GCK	NM_001354800.1	c.449T>C	p.Phe150Ser	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.449T>C	p.Phe150Ser	missense_variant	4/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 28, 2023	The GCK c.449T>C variant is classified as Likely Pathogenic (PS4_Moderate, PM2_Supporting, PS3_Supporting, PP3, PP4_Moderate). The GCK c.449T>C variant is a single nucleotide change in exon 4/10 of the GCK gene, which is predicted to change the amino acid phenylalanine at position 150 in the protein to serine. The variant has been reported multiple times in the literature in unrelated affected individuals with a clinical presentation of MODY (PMID: 30191644, 14517946, 9662401, 34789499) (PS4_Moderate). This variant is absent from population databases (PM2_Supporting). A yeast hybrid complementation functional study completed by Gersing et al, 2013 demonstrated a reduction in human GCK activity with this variant compared to non-pathogenic GCK variants/ WT control (PMID: 37101203, PS3_Supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The clinical features of this case are highly specific for the GCK gene, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4_Moderate). The variant has been reported in dbSNP (rs193922297) and in the HGMD database as disease causing (CM980893). It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 36218). -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Mar 22, 2024

The c.449T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 150 (p.(Phe150Ser)) 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 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.0.0 Popmax filtering allele frequency of 0 (below the MDEP threshold of 0.000003), and <=2 copies observed in the European non-Finnish population and any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in at least 28 unrelated individuals with hyperglycemia (PS4; PMIDs: 15305805, 30191644, internal lab contributors). This variant segregated with hyperglycemia, with at least 19 informative meioses in multiple families (PP1_Strong; internal lab contributors). Another missense variant, c.449T>A p.Phe150Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Ser has a greater Grantham distance (PM5). In summary, c.449T>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): PS4, PP1_Strong, PM2_Supporting, PP3, PP2, PM5. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2023

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30191644, 9662401, 14517946, 14517956, 18271687, 32533152, 32041611, 15305805) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.99
MutPred		0.98		.;Gain of disorder (P = 0.0172);.;.;.;
MVP		0.96
MPC		2.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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: rs193922297; hg19: chr7-44190589;