rs1554335132

chr7-44147737-G-Achr7-44147737-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000162.5(GCK):c.776C>T(p.Ala259Val) variant causes a missense change. 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A259S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 6.79

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44147738-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2578354.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-44147737-G-A is Pathogenic according to our data. Variant chr7-44147737-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447417.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.776C>T	p.Ala259Val	missense_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.87G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.776C>T	p.Ala259Val	missense_variant	7/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:2

Likely risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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 rs1554335132 in MODY, yet. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2021	The p.A259V variant (also known as c.776C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 776. The alanine at codon 259 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple individuals with a clinical and family history consistent with GCK-MODY (Tracz A et al. Exp Clin Endocrinol Diabetes, 2014 Oct;122:503-9; Borowiec M et al. Clin Genet, 2012 Dec;82:587-90). In addition, another alteration at the same codon, p.A259T (c.775G>A), has been described in multiple individuals meeting MODY diagnostic criteria (Capuano M et al. PLoS One, 2012 Jun;7:e38906; Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172); in one report, p.A259T was confirmed de novo in an individual with impaired glucose tolerance diagnosed in childhood, C-peptide secretion/detectable insulin in absence of insulin treatment, who was also negative for autoantibodies (Glotov OS et al. Mol Med Rep, 2019 Dec;20:4905-4914). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cheruvallath ZS et al. Bioorg Med Chem Lett, 2017 06;27:2678-2682). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 12, 2023

The c.776C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 259 (p.(Ala259Val)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in 15 unrelated individuals with hyperglycemia (PS4; PMID:22035297, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 16 informative meioses in 5 families (PP1_Strong; PMID: 22035297, internal lab contributors). 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). Another missense variant, c.775G>A, p.Ala259Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala259Val has a greater Grantham distance (PM5). Lastly, this variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). In summary, c. 776C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PM2_Supporting, PS4, PP1_Strong, PP2, PM5, PP4_Moderate. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.88	P;P;P;D;.
Vest4		0.95
MutPred		0.93		.;Loss of disorder (P = 0.1246);.;.;.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.97
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: rs1554335132; hg19: chr7-44187336;