NM_000162.5(GCK):c.675C>G (p.Ile225Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 14, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000657901.3

Allele description [Variation Report for NM_000162.5(GCK):c.675C>G (p.Ile225Met)]

NM_000162.5(GCK):c.675C>G (p.Ile225Met)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.675C>G (p.Ile225Met)

HGVS:

NC_000007.14:g.44149764G>C
NG_008847.2:g.53407C>G
NM_000162.5:c.675C>GMANE SELECT
NM_001354800.1:c.675C>G
NM_033507.3:c.678C>G
NM_033508.3:c.672C>G
NP_000153.1:p.Ile225Met
NP_001341729.1:p.Ile225Met
NP_277042.1:p.Ile226Met
NP_277043.1:p.Ile224Met
LRG_1074t1:c.675C>G
LRG_1074t2:c.678C>G
LRG_1074:g.53407C>G
LRG_1074p1:p.Ile225Met
LRG_1074p2:p.Ile226Met
NC_000007.13:g.44189363G>C
NM_000162.3:c.675C>G

Protein change:

I224M

Links:

dbSNP: rs772754004

NCBI 1000 Genomes Browser:

rs772754004

Molecular consequence:

NM_000162.5:c.675C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.675C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.678C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Rubrivivax sp. M9
Rubrivivax sp. M9

biosample
Roseateles depolymerans 1AA1 starved for 6h
Roseateles depolymerans 1AA1 starved for 6h

biosample
Whole genome
Whole genome

biosample
Trechispora 18S ribosomal RNA gene, partial sequence; internal transcribed space...
Trechispora 18S ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8S ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and 28S ribosomal RNA gene, partial sequence.
PopSet: 1153135607

PopSet
RecName: Full=ATP-binding cassette sub-family C member 2; AltName: Full=Canalicu...
RecName: Full=ATP-binding cassette sub-family C member 2; AltName: Full=Canalicular multidrug resistance protein; AltName: Full=Canalicular multispecific organic anion transporter 1; AltName: Full=Multidrug resistance-associated protein 2
gi|308153583|sp|Q92887.3|MRP2_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000779666	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (May 15, 2018)	germline	clinical testing	Citation Link,
SCV004295166	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11508276, 36227502, 22611063, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000779666

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(May 15, 2018)

germline

clinical testing

Citation Link,

SCV004295166

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 14, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

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

MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience.

Marucci A, Di Paola R, Rutigliano I, Fini G, Pezzilli S, Menzaghi C, Trischitta V.

Acta Diabetol. 2023 Jan;60(1):131-135. doi: 10.1007/s00592-022-01982-0. Epub 2022 Oct 13. No abstract available. Erratum in: Acta Diabetol. 2023 Mar;60(3):459. doi: 10.1007/s00592-023-02035-w.

PubMed [citation]

PMID:: 36227502

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000779666.2

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

Description

The I225M missense variant in the GCK gene has been reported previously in association with MODY (Massa et al., 2001; Beer et al., 2012). Functional studies report that I225M demonstrates an inactivating effect on enzyme activity (Beer et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016). The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (G223S/R/V, M224R/T, V226M/L/E, G227R/S/C) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this to be a pathogenic variant.

#	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, SCV004295166.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 225 of the GCK protein (p.Ile225Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 11508276, 22611063, 36227502). ClinVar contains an entry for this variant (Variation ID: 546098). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 22611063). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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