rs1332966015

Positions:

• chr7-44147831-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4 PM5_Supporting PM1 PM2_Supporting PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.682A>G variant in the glucokinase gene, GCK, causes an amino acid change of threonine to alanine at codon 228 (p.(Thr228Ala)) 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 0.931 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the East Asian subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4, PMIDs: 31638168, 12955723, internal lab contributors). Another missense variant, c.683C>T p.Thr228Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr228Ala (PM5_Supporting). In summary, c.682A>G 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, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367400790/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.97

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 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.682A>G	p.Thr228Ala	missense_variant, splice_region_variant	7/10	ENST00000403799.8
LOC105375258	XR_927223.3	n.98+83T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.682A>G	p.Thr228Ala	missense_variant, splice_region_variant	7/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250066 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Thr228Ala variant in GCK has been reported in 3 Italian individuals with Monogenic Diabetes, segregated with disease in these 3 affected relatives from 1 family (PMID: 12955723), and has been identified in 0.005442% (1/18374) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 447413). In vitro functional studies provide some evidence that the p.Thr228Ala variant may impact ATP binding (PMID: 15752705, 15102714, 19790256). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One pathogenic variant with a different amino acid change at the same position, p.Thr228Met, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 16134). Multiple variants in the same region as p.Thr228Ala have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (PMID: 22389783; Variation ID: 36244, 36243, 546098). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PM5, PM2_Supporting, PP3, PM1_Supporting, PP1 (Richards 2015). -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Feb 28, 2024	The c.682A>G variant in the glucokinase gene, GCK, causes an amino acid change of threonine to alanine at codon 228 (p.(Thr228Ala)) 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 0.931 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein's function by the ClinGen MDEP (PM1). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the East Asian subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4, PMIDs: 31638168, 12955723, internal lab contributors). Another missense variant, c.683C>T p.Thr228Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr228Ala (PM5_Supporting). In summary, c.682A>G 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, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting, PS4. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 04, 2022	This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 228 of the GCK protein (p.Thr228Ala). This missense change has been observed in individuals with clinical features of autosomal dominant GCK-related conditions (PMID: 12955723, 31638168; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr228 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22335469, 24323243, 31638168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GCK function (PMID: 15752705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 447413). -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2017

The p.T228A variant (also known as c.682A>G), located in coding exon 7 of the GCK gene, results from an A to G substitution at nucleotide position 682. The threonine at codon 228 is replaced by alanine, an amino acid with similar properties. This variant was detected in three individuals with maturity-onset diabetes of the young; all three individuals were considered related in the study, although only two were known to be related at the time of participant recruitment (Mantovani V et al. Hum. Mutat., 2003 Oct;22:338). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	.;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.49	P;P;P;P;.
Vest4		0.98
MutPred		0.99		.;Gain of catalytic residue at M224 (P = 0.0243);.;.;.;
MVP		0.99
MPC		1.1
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.99

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: rs1332966015; hg19: chr7-44187430;