7-44149810-A-T

Variant names:

• chr7-44149810-A-T
• rs80356654
• NM_000162.5:c.629T>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5 PP2 PP3 PS3_Moderate PM2_Supporting PP4_Moderate PM3_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.629T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 210 (p.(Met210Lys)) 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 0.979, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies suggest that this variant alters glucokinase kinetic parameters, with an RAI less than 0.5 (wild-type QC parameters met including ATP Km between 0.4 and 0.65) (PS3_Moderate; PMIDs: 16731834,14517946). This variant was identified in two unrelated families with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:18399931, 11372010, 27913849, internal lab contributor). At least one individual individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persisting over time) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 10 informative meioses in a family with MODY (PP1_Strong; PMIDs: 18399931, 11372010). This variant has also been detected in at least one family with neonatal diabetes. One individual in this family was homozygous and experienced permanent neonatal diabetes mellitus, and variants were were confirmed in trans (PM3_Supporting; PMIDs:18399931, 11372010). Additionally, another missense variant, c.629T>C (p.Met210Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Met210Lyshas a greater Grantham distance (PM5). In summary, c.629T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PM5, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA204367/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 9.32
• Publications: 28 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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.629T>A	p.Met210Lys	missense_variant	Exon 6 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.629T>A	p.Met210Lys	missense_variant	Exon 6 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

May 24, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 23, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM5_STR,PP1_STR,PS4_MOD,PS3_SUP,PM2_SUP,PP3 -

Permanent neonatal diabetes mellitus 1 Pathogenic:1

May 24, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Monogenic diabetes Pathogenic:1

Jul 30, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.629T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 210 (p.(Met210Lys)) 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 0.979, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies suggest that this variant alters glucokinase kinetic parameters, with an RAI less than 0.5 (wild-type QC parameters met including ATP Km between 0.4 and 0.65) (PS3_Moderate; PMIDs: 16731834,14517946). This variant was identified in two unrelated families with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:18399931, 11372010, 27913849, internal lab contributor). At least one individual individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persisting over time) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 10 informative meioses in a family with MODY (PP1_Strong; PMIDs: 18399931, 11372010). This variant has also been detected in at least one family with neonatal diabetes. One individual in this family was homozygous and experienced permanent neonatal diabetes mellitus, and variants were were confirmed in trans (PM3_Supporting; PMIDs:18399931, 11372010). Additionally, another missense variant, c.629T>C (p.Met210Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Met210Lyshas a greater Grantham distance (PM5). In summary, c.629T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PM5, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting, PM3_Supporting. -

Permanent neonatal diabetes mellitus Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.8	.;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.94
MutPred		0.97		.;Gain of ubiquitination at M210 (P = 0.0238);.;.;.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80356654; hg19: chr7-44189409;