rs1554335570

Positions:

• chr7-44150970-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000403799.8(GCK):​c.469G>A​(p.Glu157Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 O:1
• Conservation: PhyloP100: 4.10

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.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000403799.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 7-44150970-C-T is Pathogenic according to our data. Variant chr7-44150970-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447402.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=5, Uncertain_risk_allele=1}. Variant chr7-44150970-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.469G>A	p.Glu157Lys	missense_variant	4/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.472G>A	p.Glu158Lys	missense_variant	4/10		NP_277042.1
GCK	NM_033508.3	c.466G>A	p.Glu156Lys	missense_variant	5/11		NP_277043.1
GCK	NM_001354800.1	c.469G>A	p.Glu157Lys	missense_variant	4/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.469G>A	p.Glu157Lys	missense_variant	4/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 157 of the GCK protein (p.Glu157Lys). 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: 11508276, 20337973, 28726111, 29056535, 31216263; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 447402). 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 with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GCK function (PMID: 30590153). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 24, 2021	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant displayed altered enzyme kinetics compared to wild type with an increased affinity for glucose, disrupting the normal response. (PMID: 30590153) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 21, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 16602010, 14517946, 29056535, 11508276, 30590153, 31216263, 34556497, 20337973, 37292969, 28726111, 35472491, DuzkaleN2023[Article], 24430320) -

Maturity onset diabetes mellitus in young Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 06, 2017	The p.E157K variant (also known as c.469G>A), located in coding exon 4 of the GCK gene, results from a G to A substitution at nucleotide position 469. The glutamic acid at codon 157 is replaced by lysine, an amino acid with similar properties. This variant was first reported in a pediatric patient with a clinical diagnosis of MODY (Massa O et al. Diabetologia, 2001 Jul;44:898-905) and has subsequently been reported in additional MODY patients and families (Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Steele AM et al. JAMA, 2014 Jan;311:279-86). This variant was not reported in the ExAC database, with coverage at this position. 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 the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain 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 rs1554335570 in MODY, yet. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 06, 2024

Variant summary: GCK c.469G>A (p.Glu157Lys) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251460 control chromosomes (gnomAD). c.469G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (e.g. Massa_2001, Pruhova_2010, Aloi_2017, Ming_Qiang_2019, Campos Franco_2022, Mirshahi_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11508276, 16602010, 20337973, 28726111, 31216263, 35472491, 36257325). ClinVar contains an entry for this variant (Variation ID: 447402). Based on the evidence outlined above, the variant was classified as pathogenic. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T;.;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.69	.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.20	.;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.76	.;T;T;T;T
Sift4G	Benign	0.91	T;T;T;T;T
Polyphen		1.0	D;D;D;B;.
Vest4		0.70
MutPred		0.84		.;Gain of ubiquitination at E157 (P = 0.0155);.;.;.;
MVP		0.91
MPC		2.2
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1554335570; hg19: chr7-44190569; COSMIC: COSV60786442; COSMIC: COSV60786442;