NM_000162.5(GCK):c.649G>A (p.Asp217Asn) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 19, 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:: RCV001315293.9

Allele description [Variation Report for NM_000162.5(GCK):c.649G>A (p.Asp217Asn)]

NM_000162.5(GCK):c.649G>A (p.Asp217Asn)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.649G>A (p.Asp217Asn)

Other names:

NM_000162.5(GCK):c.649G>A; p.Asp217Asn

HGVS:

NC_000007.14:g.44149790C>T
NG_008847.2:g.53381G>A
NM_000162.5:c.649G>AMANE SELECT
NM_001354800.1:c.649G>A
NM_033507.3:c.652G>A
NM_033508.3:c.646G>A
NP_000153.1:p.Asp217Asn
NP_001341729.1:p.Asp217Asn
NP_277042.1:p.Asp218Asn
NP_277043.1:p.Asp216Asn
LRG_1074t1:c.649G>A
LRG_1074t2:c.652G>A
LRG_1074:g.53381G>A
LRG_1074p1:p.Asp217Asn
LRG_1074p2:p.Asp218Asn
NC_000007.13:g.44189389C>T
NM_000162.3:c.649G>A

Protein change:

D216N

Links:

dbSNP: rs147065275

NCBI 1000 Genomes Browser:

rs147065275

Molecular consequence:

NM_000162.5:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.646G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001505862	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22611063, 27913849, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001505862

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 19, 2023)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis.

Beer NL, Osbak KK, van de Bunt M, Tribble ND, Steele AM, Wensley KJ, Edghill EL, Colcough K, Barrett A, Valentínová L, Rundle JK, Raimondo A, Grimsby J, Ellard S, Gloyn AL.

Diabetes Care. 2012 Jul;35(7):1482-4. doi: 10.2337/dc11-2420. Epub 2012 May 18.

PubMed [citation]

PMID:: 22611063
PMCID:: PMC3379612

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry.

Johansson BB, Irgens HU, Molnes J, Sztromwasser P, Aukrust I, Juliusson PB, Søvik O, Levy S, Skrivarhaug T, Joner G, Molven A, Johansson S, Njølstad PR.

Diabetologia. 2017 Apr;60(4):625-635. doi: 10.1007/s00125-016-4167-1. Epub 2016 Dec 2.

PubMed [citation]

PMID:: 27913849

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001505862.4

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

Description

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GCK function (PMID: 22611063). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 911631). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22611063, 27913849). This variant is present in population databases (rs147065275, gnomAD 0.3%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 217 of the GCK protein (p.Asp217Asn).

#	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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