rs1554334478

chr7-44145279-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Strong

The NM_000162.5(GCK):c.1255T>C(p.Phe419Leu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F419S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense, splice_region
• Scores: Splicing: ADA: 0.8315
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 8.77

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr7-44145278-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2571658.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-44145279-A-G is Pathogenic according to our data. Variant chr7-44145279-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 447388.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.1255T>C	p.Phe419Leu	missense_variant, splice_region_variant	10/10	ENST00000403799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.1255T>C	p.Phe419Leu	missense_variant, splice_region_variant	10/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

GCK-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

The GCK c.1255T>C variant is predicted to result in the amino acid substitution p.Phe419Leu. This variant has been reported in individuals with maturity-onset diabetes of the young (MODY) (Inoue et al. 2004. PubMed ID: 15102714; Pinterova et al. 2007. PubMed ID: 17204055; Supplemental Table S1, Osbak et al. 2009. PubMed ID: 19790256; Pruhova et al. 2010. PubMed ID: 20337973) and in individuals with asymptomatic hyperglycemia (Feigerlová et al. 2006. PubMed ID: 16602010). Of note, this variant was identified in one family with MODY, however the variant was 83.3% penetrant in that family (Inoue et al. 2004. 15102714). The p.Phe419Leu variant was detected near a putative MgATP binding site and could thus affect binding kinetics (Pinterova et al. 2007. PubMed ID: 17204055). Other variants impacting the p.Phe419 amino acid have also been reported in individuals with MODY (p.Phe419Val, Supplemental Table S1, Osbak et al. 2009. PubMed ID: 19790256; p.Phe419Ser, Valentínová et al. 2012. PubMed ID: 22493702; p.Phe419Cys, Haliloglu et al. 2016. PubMed ID: 27256595). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we interpret the c.1255T>C (p.Phe419Leu) variant as likely pathogenic. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, 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 rs1554334478 in MODY, yet. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 12, 2017

- -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 26, 2023

The c.1255T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 419 (p.(Phe419Leu)) of NM_000162.5. 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 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 17204055, 20337973, 16602010, internal lab contributors). One of these individuals had a clinical history consistent with GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 17204055, 20337973, 16602010). Another missense variant, c.1256T>C p.Phe419Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	34
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;D;T;.;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.0030	D;T;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.89
MutPred		0.97		.;.;Loss of methylation at K420 (P = 0.0308);.;.;.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.13		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: rs1554334478; hg19: chr7-44184878;