chr7-44150006-A-G

Variant names:

• chr7-44150006-A-G
• rs193922306
• NM_000162.5:c.542T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000162.5(GCK):​c.542T>C​(p.Val181Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 9.32
• Publications: 5 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 10 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 274 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.069 (below the threshold of 3.09). Trascript score misZ: 2.7821 (below the threshold of 3.09). GenCC associations: The gene is linked to transient neonatal diabetes mellitus, monogenic diabetes, permanent neonatal diabetes mellitus 1, diabetes mellitus, noninsulin-dependent, maturity-onset diabetes of the young type 2, hyperinsulinism due to glucokinase deficiency, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-44150006-A-G is Pathogenic according to our data. Variant chr7-44150006-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36228.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.542T>C	p.Val181Ala	missense_variant	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.542T>C	p.Val181Ala	missense_variant	Exon 5 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 181 of the GCK protein (p.Val181Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 11508276; Invitae). ClinVar contains an entry for this variant (Variation ID: 36228). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. This variant disrupts the p.Val181 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 33477506), which suggests that this may be a clinically significant amino acid residue. 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. -

Aug 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 14517946, 11508276, 33477506) -

Jun 18, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Pathogenic:2

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely risk allele

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs193922306 in MODY, yet. -

Jun 13, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V181A variant (also known as c.542T>C), located in coding exon 5 of the GCK gene, results from a T to C substitution at nucleotide position 542. The valine at codon 181 is replaced by alanine, an amino acid with similar properties. This variant was reported in an Italian pediatric proband with a clinical diagnosis of maturity onset diabetes of the young (MODY) and was reported to segregate with disease in the family; however, how many family members were tested was not specified; in addition, no other MODY genes were analyzed (Massa O et al. Diabetologia, 2001 Jul;44:898-905). This variant has been reported in MODY cohorts (Ivanoshchuk DE et al. J Pers Med, 2021 Jan;11:; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). Based on internal structural analysis, this alteration is likely to disrupt the catalytic properties of this enzyme (Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is likely pathogenic for GCK-related maturity onset diabetes of the young (MODY); however, it is unlikely to be causative of GCK-related hyperinsulinemic hypolycemia. -

Maturity-onset diabetes of the young type 2 Pathogenic:1

Aug 18, 2011

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T;.;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.
PhyloP100		9.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.9	.;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.12	B;B;B;B;.
Vest4		0.89
MutPred		0.95		.;Gain of disorder (P = 0.0448);.;.;.;
MVP		0.98
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922306; hg19: chr7-44189605;