7-44145608-A-C

Position:

• chr7-44145608-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM5 PS4_Moderate PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1142T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 381 (p.(Met381Arg)) 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 0.9629, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 22060211 (likely same cases as PMID 29927023, PMID 32375122, PMID 2555642, and PMID 24804978 (Kawakita et al 2014)), PMID 24804978, internal lab contributors). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Arg has a greater Grantham distance (PM5). In summary, the c.1142T>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PM5, PS4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213719/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.40

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1142T>G	p.Met381Arg	missense_variant	9/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1142T>G	p.Met381Arg	missense_variant	9/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Jul 17, 2023	The c.1142T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 381 (p.(Met381Arg)) 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 0.9629, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 22060211 (likely same cases as PMID 29927023, PMID 32375122, PMID 2555642, and PMID 24804978 (Kawakita et al 2014)), PMID 24804978, internal lab contributors). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Arg has a greater Grantham distance (PM5). In summary, the c.1142T>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PM5, PS4_Moderate, PP2, PP3, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2022	Variant summary: GCK c.1142T>G (p.Met381Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Other missense variants at the same codon, namely, c.1142T>A (p.Met381Lys) and c.1142T>C (p.Met381Thr) have been observed in association with Maturity Onset Diabetes Of The Young supporting the critical relevance of this residue. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235544 control chromosomes. c.1142T>G has been reported in the literature in at-least three individuals affected with Maturity Onset Diabetes Of The Young 2 who have been subsequently cited by others (example, Yorifuji_2012/2018, Zhou_2020, Bennett_2015, Kawakita_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, the ClinGen Monogenic Diabetes Expert Panel has classified this variant as Likely Pathogenic, citing overlapping evidence utilized in the context of this evaluation (personal correspondence). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;D;D;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	.;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.92
MutPred		0.90		.;.;Gain of MoRF binding (P = 0.0144);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs193922266; hg19: chr7-44185207;