rs104894006

Positions:

• chr7-44149992-G-A
• chr7-44149992-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000162.5(GCK):​c.556C>T​(p.Arg186*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,654 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GCK NM_000162.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.979

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]

GCK (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-44149992-G-A is Pathogenic according to our data. Variant chr7-44149992-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44149992-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.556C>T	p.Arg186*	stop_gained	5/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.559C>T	p.Arg187*	stop_gained	5/10		NP_277042.1
GCK	NM_033508.3	c.553C>T	p.Arg185*	stop_gained	6/11		NP_277043.1
GCK	NM_001354800.1	c.556C>T	p.Arg186*	stop_gained	5/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.556C>T	p.Arg186*	stop_gained	5/10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461654 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727100

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 23, 2019	This sequence change creates a premature termination codon at position 186 in exon 5 (of 10) of GCK (p.Arg186*). It is expected to result in an absent or disrupted protein product (PVS1). Loss of function is an established mechanism of disease for GCK-associated disease. The variant is absent in a large population cohort (rs104894006, gnomAD v2.1 - PM2). It has been identified heterozygous in at least two probands diagnosed with maturity-onset diabetes of the young (MODY, PMID: 9049484, 15841481 - PS4_Supporting), and segregates with MODY or late-onset non-insulin-dependent diabetes mellitus (NIDDM) in multiple affected individuals in at least two families (PMID: 1360036, 8094163 - PP1_Strong). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Sep 29, 2022	ACMG Criteria: PVS1, PM2, PP1, PP5; Variant was found in heterozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2024	Variant summary: GCK c.556C>T (p.Arg186X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD v2.1 is considered unreliable, as metrics indicate poor data quality at this position. However, the variant was found at a frequency of 6.8e-6 in 1461654 chromosomes in gnomAD v4.0. c.556C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young (e.g. Yorifuji_2023). The following publications have been ascertained in the context of this evaluation (PMID: 1360036, 15841481, 8068341, 8094164, 8094163, 8096296, 17573900, 18271687, 36504295). ClinVar contains an entry for this variant (Variation ID: 16133). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Geisinger Clinic, Geisinger Health System	Aug 02, 2022	PVS1, PM2, PP1_Strong, PS4, PP4 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change creates a premature translational stop signal (p.Arg186*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GCK-related conditions (PMID: 1360036, 30191644, 30257192). ClinVar contains an entry for this variant (Variation ID: 16133). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2024	This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with MODY. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17573900, 18271687, 8094164, 1397713, 30257192, 8094163, 26641800, 27269892, 22060211, 8168652, 33046911, 15841481, 24952377, 19002431, 8433729, 24430320, 30191644, 20337973, 33852230, 21348868, 30665703, 9049484, 24660669, 32533152, 1360036) -

Maturity onset diabetes mellitus in young Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2017	The p.R186* pathogenic mutation (also known as c.556C>T), located in coding exon 5 of the GCK gene, results from a C to T substitution at nucleotide position 556. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in numerous maturity-onset diabetes of the young (MODY) families (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The p.Arg185Ter in GCK (also known as p.Arg186X) has been reported in at least 6 individuals with maturity onset diabetes of the young (MODY) and segregated with disease in at least 15 affected individuals from 4 families (Estalella 2007 PMID: 17573900, Toaima 2005 PMID: 15841481, Velho 1997 PMID: 9049484, Froguel 1993 PMID: 8433729, Froguel 1993 PMID: 8094163, Katagiri 1992 PMID: 1360036). Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (ClinVar Variation ID: 16133). This nonsense variant leads to a premature termination codon at position 185, which is predicted to lead to a truncated or absent protein. Loss of function of the GCK gene is an established disease mechanism in autosomal dominant maturity onset diabetes of the young. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PS4_Moderate. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 06, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.43	N
Vest4		0.97
GERP RS		-2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 2
DS_DL_spliceai		0.21		Position offset: -23

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894006; hg19: chr7-44189591;