NM_000162.5(GCK):c.469G>A (p.Glu157Lys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: May 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000517004.22

Allele description [Variation Report for NM_000162.5(GCK):c.469G>A (p.Glu157Lys)]

NM_000162.5(GCK):c.469G>A (p.Glu157Lys)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.469G>A (p.Glu157Lys)

HGVS:

NC_000007.14:g.44150970C>T
NG_008847.2:g.52201G>A
NM_000162.5:c.469G>AMANE SELECT
NM_001354800.1:c.469G>A
NM_033507.3:c.472G>A
NM_033508.3:c.466G>A
NP_000153.1:p.Glu157Lys
NP_001341729.1:p.Glu157Lys
NP_277042.1:p.Glu158Lys
NP_277043.1:p.Glu156Lys
LRG_1074t1:c.469G>A
LRG_1074t2:c.472G>A
LRG_1074:g.52201G>A
LRG_1074p1:p.Glu157Lys
LRG_1074p2:p.Glu158Lys
NC_000007.13:g.44190569C>T
NM_000162.3:c.469G>A
p.GLU157LYS

Protein change:

E156K

Links:

dbSNP: rs1554335570

NCBI 1000 Genomes Browser:

rs1554335570

Molecular consequence:

NM_000162.5:c.469G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.469G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.472G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.466G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613433	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Feb 24, 2021)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 29056535, 28726111, 20337973, 11508276, 16602010, 31216263, 30590153, 14517946, 26467025
SCV001794264	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (May 13, 2024)	germline	clinical testing	Citation Link,
SCV002069052	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002268185	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11508276, 20337973, 28726111, 29056535, 31216263, 30590153, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents.

Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, Cerná M, Pedersen O, Hansen T.

Eur J Pediatr. 2006 Jul;165(7):446-52. Epub 2006 Apr 7.

PubMed [citation]

PMID:: 16602010

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Gloyn AL.

Hum Mutat. 2003 Nov;22(5):353-62. Review.

PubMed [citation]

PMID:: 14517946

See all PubMed Citations (11)

Details of each submission

From Athena Diagnostics, SCV000613433.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001794264.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002069052.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002268185.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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