NM_000162.5(GCK):c.617C>T (p.Thr206Met) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 2, 2023
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:: RCV001553149.25

Allele description [Variation Report for NM_000162.5(GCK):c.617C>T (p.Thr206Met)]

NM_000162.5(GCK):c.617C>T (p.Thr206Met)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.617C>T (p.Thr206Met)

HGVS:

NC_000007.14:g.44149822G>A
NG_008847.2:g.53349C>T
NM_000162.5:c.617C>TMANE SELECT
NM_001354800.1:c.617C>T
NM_033507.3:c.620C>T
NM_033508.3:c.614C>T
NP_000153.1:p.Thr206Met
NP_001341729.1:p.Thr206Met
NP_277042.1:p.Thr207Met
NP_277043.1:p.Thr205Met
LRG_1074t1:c.617C>T
LRG_1074t2:c.620C>T
LRG_1074:g.53349C>T
LRG_1074p1:p.Thr206Met
LRG_1074p2:p.Thr207Met
NC_000007.13:g.44189421G>A
NM_000162.3:c.617C>T

Protein change:

T205M

Links:

dbSNP: rs1441649062

NCBI 1000 Genomes Browser:

rs1441649062

Molecular consequence:

NM_000162.5:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.620C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.614C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001773965	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 27, 2021)	germline	clinical testing	Citation Link,
SCV002072031	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 17, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002179995	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11508276, 15928245, 31216263, 16173921, 28492532
SCV003917147	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI.

Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, Cherubini V, Guazzarotti L, Sulli N, Matschinsky FM, Lorini R, Iafusco D, Barbetti F; Diabetes Study Group of the Italian Society of Paediatic Endocrinology and Diabetes (SIEDP)..

Diabetologia. 2001 Jul;44(7):898-905.

PubMed [citation]

PMID:: 11508276

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV001773965.3

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

Description

Published functional studies demonstrate a damaging effect, specifically enzymatic assays reveal an activity index corresponding to 0.2% of wildtype GK activity (Galn et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 11508276, 12955723, 15841481, 16173921, 29927023, 29056535, 28726111, 28170077, 31216263)

#	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, SCV002072031.1

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

Description

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.617C>T, in exon 6 that results in an amino acid change, p.Thr206Met. The p.Thr206Met change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Thr206Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Thr206Met sequence change has previously been described in multiple patients with GCK-related maturity onset diabetes of the young (MODY) (PMIDs: 24606082, 2014, 11508276). Several other pathogenic sequence changes affecting the same p.Thr206 amino acid (p.Thr206Arg, p.Thr206Lys, p.Thr206Ala, and p.Thr206Pro) have been reported in patients with GCK-MODY (PMIDs: 19790256, 17937063, 12442280, 24405491). Furthermore, functional studies of the p.Thr206Met sequence change demonstrated that it results in severe loss of function (PMID: 24606082).

#	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, SCV002179995.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 206 of the GCK protein (p.Thr206Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (MODY) (PMID: 11508276, 15928245, 16173921, 31216263). ClinVar contains an entry for this variant (Variation ID: 1191898). 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 expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 16173921). 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

From CeGaT Center for Human Genetics Tuebingen, SCV003917147.13

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

Description

GCK: PM1, PM2, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting

#	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		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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