NM_000162.5(GCK):c.971T>C (p.Leu324Pro) AND Maturity-onset diabetes of the young type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000029933.3

Allele description [Variation Report for NM_000162.5(GCK):c.971T>C (p.Leu324Pro)]

NM_000162.5(GCK):c.971T>C (p.Leu324Pro)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.971T>C (p.Leu324Pro)

HGVS:

NC_000007.14:g.44146511A>G
NG_008847.2:g.56660T>C
NM_000162.5:c.971T>CMANE SELECT
NM_001354800.1:c.971T>C
NM_001354801.1:c.8+108T>C
NM_033507.3:c.974T>C
NM_033508.3:c.968T>C
NP_000153.1:p.Leu324Pro
NP_001341729.1:p.Leu324Pro
NP_277042.1:p.Leu325Pro
NP_277043.1:p.Leu323Pro
LRG_1074t1:c.971T>C
LRG_1074t2:c.974T>C
LRG_1074:g.56660T>C
LRG_1074p1:p.Leu324Pro
LRG_1074p2:p.Leu325Pro
NC_000007.13:g.44186110A>G
NM_000162.3:c.971T>C

Protein change:

L323P

Links:

dbSNP: rs193922341

NCBI 1000 Genomes Browser:

rs193922341

Molecular consequence:

NM_001354801.1:c.8+108T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000162.5:c.971T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.971T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.974T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.968T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maturity-onset diabetes of the young type 2
Synonyms:: MODY type 2; Diabetes mellitus MODY type 2; MODY glucokinase-related; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007453; MedGen: C0342277; Orphanet: 552; OMIM: 125851

Recent activity

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uncharacterized protein HG536_0D03470 [Torulaspora globosa]
uncharacterized protein HG536_0D03470 [Torulaspora globosa]
gi|1929633825|ref|XP_037139499.1|

Protein
LOC127265710 [Andrographis paniculata]
LOC127265710 [Andrographis paniculata]
Gene ID:127265710

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052588	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15305805, 20005544, 34746319, 36227502, 36257325 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000052588

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 12, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY).

McKinney JL, Cao H, Robinson JF, Metzger DL, Cummings E, Riddell DC, Sanderson SR, Pacaud D, Ho J, Hegele RA.

Clin Invest Med. 2004 Jun;27(3):135-41.

PubMed [citation]

PMID:: 15305805

Effects of glucose and insulin on acyl ghrelin and desacyl ghrelin, leptin, and adiponectin in pregnant women with diabetes.

Gibson W, Liu J, Gaylinn B, Thorner MO, Meneilly GS, Babich SL, Thompson D, Chanoine JP.

Metabolism. 2010 Jun;59(6):841-7. doi: 10.1016/j.metabol.2009.09.033. Epub 2009 Dec 16.

PubMed [citation]

PMID:: 20005544
PMCID:: PMC2975459

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052588.3

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

Description

Variant summary: GCK c.971T>C (p.Leu324Pro) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246806 control chromosomes (gnomAD). c.971T>C has been reported in the literature in multiple individuals affected with Maturity-Onset Diabetes of the Young (McKinney_2004, Katashima_2021, Mirshahi_2022, Marucci_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15305805, 20005544, 34746319, 36257325, 36227502). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was 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: May 7, 2024

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