NM_000162.5(GCK):c.562G>A (p.Ala188Thr) AND Maturity-onset diabetes of the young type 2

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 1, 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:: RCV001248939.7

Allele description [Variation Report for NM_000162.5(GCK):c.562G>A (p.Ala188Thr)]

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

HGVS:

NC_000007.14:g.44149986C>T
NG_008847.2:g.53185G>A
NM_000162.5:c.562G>AMANE SELECT
NM_001354800.1:c.562G>A
NM_033507.3:c.565G>A
NM_033508.3:c.559G>A
NP_000153.1:p.Ala188Thr
NP_001341729.1:p.Ala188Thr
NP_277042.1:p.Ala189Thr
NP_277043.1:p.Ala187Thr
LRG_1074t1:c.562G>A
LRG_1074t2:c.565G>A
LRG_1074:g.53185G>A
LRG_1074p1:p.Ala188Thr
LRG_1074p2:p.Ala189Thr
NC_000007.13:g.44189585C>T
NC_000007.13:g.44189585C>T
NM_000162.3:c.562G>A

Protein change:

A187T

Links:

dbSNP: rs751279776

NCBI 1000 Genomes Browser:

rs751279776

Molecular consequence:

NM_000162.5:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Sus scrofa]
PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Sus scrofa]
Gene ID:106504748

Gene
Adenoidectomy
Adenoidectomy
Excision of the adenoids. (Dorland, 28th ed)<br/>

MeSH
Skin Diseases, Papulosquamous
Skin Diseases, Papulosquamous
A group of dermatoses with distinct morphologic features. The primary lesion is most commonly a papule, usually erythematous, with a variable degree of scaling on the surface....<br/>Year introduced: 1993

MeSH
Profile neighbors for GEO Profiles (Select 78877865) (200)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 78825548) (20)
GEO Profiles

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422718	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 (6) [See all records that cite these PMIDs] 30257192, 12955723, 12050210, 8314448, 14517956, 25741868 Citation Link,
SCV002562179	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
SCV002573171	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16965331, 31968686, 19790256, 30257192, 12050210, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422718

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 (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002562179

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]

SCV002573171

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (6)
[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	3	not provided	not provided	1	not provided	research, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.

Mantovani V, Salardi S, Cerreta V, Bastia D, Cenci M, Ragni L, Zucchini S, Parente R, Cicognani A.

Hum Mutat. 2003 Oct;22(4):338.

PubMed [citation]

PMID:: 12955723

Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family.

Shimada F, Makino H, Hashimoto N, Taira M, Seino S, Bell GI, Kanatsuka A, Yoshida S.

Diabetologia. 1993 May;36(5):433-7.

PubMed [citation]

PMID:: 8314448

See all PubMed Citations (10)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422718.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Ala188Thr variant in GCK has been reported in 2 homozygous Egyptian individuals and 2 heterozygous Egyptian individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 1 family (DOI: 10.1007/s13410-018-0658-6), and has been identified in 0.005% (1/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751279776). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. 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 vitro functional studies provide some evidence that the p.Ala188Thr variant may slightly impact protein function (PMID: 30257192). However, these types of assays may not accurately represent biological function. The p.Ala188Thr variant is located in a region of GCK that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30257192). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease and more affected individuals with the variant than expected. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PM1_Supporting, PS3_Supporting (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, SCV002562179.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From 3billion, SCV002573171.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 30257192). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000804849). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 30257192). Different missense changes at the same codon (p.Ala188Glu, p.Ala188Gly, p.Ala188Pro, p.Ala188Val) have been reported to be associated with GCK -related disorder (ClinVar ID: VCV000036229 / PMID: 12050210 , 16965331 , 19790256 , 31968686). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: May 7, 2024

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