7-44145618-C-G

Variant names:

• chr7-44145618-C-G
• rs104894016
• NM_000162.5:c.1132G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM5_Strong PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1132G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 378 (p.(Ala378Pro)) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, there is only 1 filtered allele present (≤ 1 copy in any subpopulation), thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting) GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The c.1133C>T, p.(Ala378Val) and c.1132G>A, p.(Ala378Thr) variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 22035297, 24918535, internal lab contributor). One of these individuals had HbA1c 5.6 - 7.6%; however, the fasting glucose exceeded mmol/L, and PP4 could not be applied, and there was insufficient clinical data provided for the other individual to evaluate for PP4 (PMIDs: 22035297, 24918535; internal lab contributor). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 22035297). In summary, c.1132G>C 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): PM2_Supporting, PP2, PP3, PM5_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398808/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 3.27

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 7 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1132G>C	p.Ala378Pro	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1132G>C	p.Ala378Pro	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454616 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723670

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Oct 03, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1132G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 378 (p.(Ala378Pro)) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, there is only 1 filtered allele present (less than or equal to 1 copy in any subpopulation), thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting) GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The c.1133C>T, p.(Ala378Val) and c.1132G>A, p.(Ala378Thr) variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 22035297, 24918535, internal lab contributor). One of these individuals had HbA1c 5.6 - 7.6%; however, the fasting glucose exceeded mmol/L, and PP4 could not be applied, and there was insufficient clinical data provided for the other individual to evaluate for PP4 (PMIDs: 22035297, 24918535; internal lab contributor). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 22035297). In summary, c.1132G>C 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): PM2_Supporting, PP2, PP3, PM5_Strong. -

not provided Uncertain:1

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 378 of the GCK protein (p.Ala378Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22035297). ClinVar contains an entry for this variant (Variation ID: 2628365). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;.;H;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	.;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0050	.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.98
MutPred		0.96		.;.;Loss of MoRF binding (P = 0.0655);.;.;.;
MVP		0.98
MPC		2.5
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: rs104894016; hg19: chr7-44185217;