NM_000162.5(GCK):c.748C>T (p.Arg250Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000517148.10

Allele description [Variation Report for NM_000162.5(GCK):c.748C>T (p.Arg250Cys)]

NM_000162.5(GCK):c.748C>T (p.Arg250Cys)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.748C>T (p.Arg250Cys)

Other names:

NM_000162.5(GCK):c.748C>T

HGVS:

NC_000007.14:g.44147765G>A
NG_008847.2:g.55406C>T
NM_000162.5:c.748C>TMANE SELECT
NM_001354800.1:c.748C>T
NM_033507.3:c.751C>T
NM_033508.3:c.745C>T
NP_000153.1:p.Arg250Cys
NP_001341729.1:p.Arg250Cys
NP_277042.1:p.Arg251Cys
NP_277043.1:p.Arg249Cys
LRG_1074t1:c.748C>T
LRG_1074t2:c.751C>T
LRG_1074:g.55406C>T
LRG_1074p1:p.Arg250Cys
LRG_1074p2:p.Arg251Cys
NC_000007.13:g.44187364G>A
NC_000007.13:g.44187364G>A
NM_000162.3(GCK):c.748C>T
NM_000162.3:c.748C>T
p.ARG250CYS
p.Arg250Cys

Protein change:

R249C

Links:

dbSNP: rs1057524904

NCBI 1000 Genomes Browser:

rs1057524904

Molecular consequence:

NM_000162.5:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.751C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.745C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens golgin A6 family member B (GOLGA6B), mRNA
Homo sapiens golgin A6 family member B (GOLGA6B), mRNA
gi|94538358|ref|NM_018652.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613453	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Likely pathogenic (Nov 13, 2020)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28842611, 30245511, 19790256, 17204055, 20337973, 19069349, 26467025
SCV002319079	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 15, 2022)	germline	clinical testing	Citation Link,
SCV003439947	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17204055, 19069349, 23771925, 30155490, 30245511, 36257325, 19564454, 30592380, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613453

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Likely pathogenic
(Nov 13, 2020)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002319079

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Mar 15, 2022)

germline

clinical testing

Citation Link,

SCV003439947

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (9)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evidence-based tailoring of bioinformatics approaches to optimize methods that predict the effects of nonsynonymous amino acid substitutions in glucokinase.

Šimčíková D, Kocková L, Vackářová K, Těšínský M, Heneberg P.

Sci Rep. 2017 Aug 25;7(1):9499. doi: 10.1038/s41598-017-09810-0.

PubMed [citation]

PMID:: 28842611
PMCID:: PMC5573313

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.

Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL.

Hum Mutat. 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. Review.

PubMed [citation]

PMID:: 19790256

See all PubMed Citations (13)

Details of each submission

From Athena Diagnostics, SCV000613453.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant did not appear to affect the function of the protein when compared to wild-type; however, not all possible impacts on the protein were assayed, such as inhibitor binding or thermostability (PMID: 28842611). Computational tools predict that this variant is damaging.

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

From GeneDx, SCV002319079.2

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

Description

Identified in unrelated patients with suspected MODY, hyperglycemia, or diabetes, however, patient-specific clinical information not provided (Pinterova et al., 2007; Lorini et al., 2009; Ma et al., 2019; Bonnefond et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19069349, 30245511, 20337973, 19790256, 33046911, 28842611, 32375122, 17204055, 19564454)

#	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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439947.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the GCK protein (p.Arg250Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 17204055, 19069349, 23771925, 30155490, 30245511, 36257325; Invitae). ClinVar contains an entry for this variant (Variation ID: 393451). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg250 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 19564454, 30592380), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been 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: Oct 13, 2024

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