NM_000162.5(GCK):c.627GAT[3] (p.Met210_Ile211insMet) AND Maturity onset diabetes mellitus in young

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 18, 2024
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:: RCV002368789.3

Allele description [Variation Report for NM_000162.5(GCK):c.627GAT[3] (p.Met210_Ile211insMet)]

NM_000162.5(GCK):c.627GAT[3] (p.Met210_Ile211insMet)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.627GAT[3] (p.Met210_Ile211insMet)

HGVS:

NC_000007.14:g.44149807ATC[3]
NG_008847.2:g.53359GAT[3]
NM_000162.3:c.630_632dup
NM_000162.5:c.627GAT[3]MANE SELECT
NM_001354800.1:c.627GAT[3]
NM_033507.3:c.630GAT[3]
NM_033508.3:c.624GAT[3]
NP_000153.1:p.Met210_Ile211insMet
NP_001341729.1:p.Met210_Ile211insMet
NP_277042.1:p.Met211_Ile212insMet
NP_277043.1:p.Met209_Ile210insMet
LRG_1074t1:c.627GAT[3]
LRG_1074t2:c.630GAT[3]
LRG_1074:g.53359GAT[3]
LRG_1074p1:p.Met210_Ile211insMet
LRG_1074p2:p.Met211_Ile212insMet
NC_000007.13:g.44189405_44189406insATC
NC_000007.13:g.44189406ATC[3]
NM_000162.3:c.630_632dupGAT
NM_000162.5:c.630_632dupGATMANE SELECT

Molecular consequence:

NM_000162.5:c.627GAT[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001354800.1:c.627GAT[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_033507.3:c.630GAT[3] - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_033508.3:c.624GAT[3] - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Name:: Maturity onset diabetes mellitus in young (MODY)
Synonyms:: Mason type diabetes
Identifiers:: MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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1870436[uid] (1)
Taxonomy
RecName: Full=Epsin-1; AltName: Full=EH domain-binding mitotic phosphoprotein; A...
RecName: Full=Epsin-1; AltName: Full=EH domain-binding mitotic phosphoprotein; AltName: Full=EPS-15-interacting protein 1
gi|332278179|sp|Q9Y6I3.2|EPN1_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002660982	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15016359, 22101819, 31063852 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002660982

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 18, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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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

Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase.

Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y.

Structure. 2004 Mar;12(3):429-38.

PubMed [citation]

PMID:: 15016359

The active conformation of human glucokinase is not altered by allosteric activators.

Petit P, Antoine M, Ferry G, Boutin JA, Lagarde A, Gluais L, Vincentelli R, Vuillard L.

Acta Crystallogr D Biol Crystallogr. 2011 Nov;67(Pt 11):929-35. doi: 10.1107/S0907444911036729. Epub 2011 Oct 19.

PubMed [citation]

PMID:: 22101819

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002660982.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.630_632dupGAT variant (also known as p.M210dup), located in coding exon 6 of the GCK gene, results from an in-frame duplication of GAT at nucleotide positions 630 to 632. This results in the duplication of an extra residue between codons 210 and 211. This alteration was detected in two unrelated families with maturity-onset diabetes of the young (MODY) (Sanyoura M et al. Diabetes Res Clin Pract, 2019 May;151:231-236; personal communication with Dr. Sanyoura). Based on internal structural analysis, the duplication is located in an allosteric site of glucokinase and is more deleterious than nearby pathogenic variants (Kamata K et al. Structure, 2004 Mar;12:429-38; Petit P et al. Acta Crystallogr D Biol Crystallogr, 2011 Nov;67:929-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be 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: Oct 26, 2024

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