7-44149992-G-A

Variant names:

• chr7-44149992-G-A
• rs104894006
• NM_000162.5:c.556C>T

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R186R) has been classified as Likely benign. 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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 16133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.556C>T	p.Arg186*	stop_gained	Exon 5 of 10	ENST00000403799.8	NP_000153.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251082 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000771 Hom.: 0

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

Mar 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 29, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1, PM2, PP1, PP5; Variant was found in heterozygous state. -

Aug 02, 2022

Geisinger Clinic, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PM2, PP1_Strong, PS4, PP4 -

Nov 23, 2019

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 08, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 06, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 07, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Type 2 diabetes mellitus Pathogenic:1

Feb 06, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		0.98
Vest4		0.97
GERP RS		-2.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894006; hg19: chr7-44189591;