NM_000162.5(GCK):c.544G>A (p.Val182Met) AND Maturity-onset diabetes of the young type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 2, 2022
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:: RCV001248908.8

Allele description [Variation Report for NM_000162.5(GCK):c.544G>A (p.Val182Met)]

NM_000162.5(GCK):c.544G>A (p.Val182Met)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.544G>A (p.Val182Met)

HGVS:

NC_000007.14:g.44150004C>T
NG_008847.2:g.53167G>A
NM_000162.5:c.544G>AMANE SELECT
NM_001354800.1:c.544G>A
NM_033507.3:c.547G>A
NM_033508.3:c.541G>A
NP_000153.1:p.Val182Met
NP_001341729.1:p.Val182Met
NP_277042.1:p.Val183Met
NP_277043.1:p.Val181Met
LRG_1074t1:c.544G>A
LRG_1074t2:c.547G>A
LRG_1074:g.53167G>A
LRG_1074p1:p.Val182Met
LRG_1074p2:p.Val183Met
NC_000007.13:g.44189603C>T
NC_000007.13:g.44189603C>T
NM_000162.3(GCK):c.544G>A
NM_000162.3:c.544G>A
P35557:p.Val182Met
p.VAL182MET

Protein change:

V181M

Links:

UniProtKB: P35557#VAR_003699; dbSNP: rs587780345

NCBI 1000 Genomes Browser:

rs587780345

Molecular consequence:

NM_000162.5:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.547G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.541G>A - 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

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EL272_RS03990 [Arachnia propionica]
EL272_RS03990 [Arachnia propionica]
Gene ID:64406294

Gene
Ultrasonography, Mammary
Ultrasonography, Mammary
Use of ultrasound for imaging the breast. The most frequent application is the diagnosis of neoplasms of the female breast.<br/>Year introduced: 1991

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422601	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 21395678, 18056790, 23771172, 25082184, 25494859, 15102714, 29510678, 20337973, 25306193, 25741868 Citation Link,
SCV002562177	Geisinger Clinic, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2022)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 36257325

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422601

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 22, 2020)

germline

curation

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV002562177

Geisinger Clinic, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 2, 2022)

germline

research

PubMed (2)
[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	5	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.

McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, Williams A, Hattersley AT, Ellard S.

Diabet Med. 2011 Sep;28(9):1028-33. doi: 10.1111/j.1464-5491.2011.03287.x.

PubMed [citation]

PMID:: 21395678

Diabetes models by screen for hyperglycemia in phenotype-driven ENU mouse mutagenesis projects.

Aigner B, Rathkolb B, Herbach N, Hrabé de Angelis M, Wanke R, Wolf E.

Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E232-40. Epub 2007 Dec 4. Review.

PubMed [citation]

PMID:: 18056790

See all PubMed Citations (11)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422601.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

The p.Val182Met variant in GCK has been reported in at least 9 individuals with maturity-onset diabetes of the young (MODY) type 2, segregated with disease in 4 affected relatives from 2 families (PMID: 29510678, 20337973, 21395678, 25082184, 23771172, 25306193, 25494859), and was absent from large population studies. Animal models in mice have shown that this variant causes MODY type 2 (15102714, 18056790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for MODY type 2 in an autosomal dominant manner based on the phenotype of mouse models being consistent with human disease, the increased prevalence of the variant in affected individuals, including relatives, compared to controls, and computational evidence. ACMG/AMP Criteria applied: PS3_PM2, PS4_moderate, PP3, PP1 (Richards 2015).

#	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 Geisinger Clinic, Geisinger Health System, SCV002562177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	research	PubMed (2)

Description

PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3

#	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		5	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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