NM_000162.5(GCK):c.1099G>A (p.Val367Met) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 21, 2024
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:: RCV000440624.7

Allele description [Variation Report for NM_000162.5(GCK):c.1099G>A (p.Val367Met)]

NM_000162.5(GCK):c.1099G>A (p.Val367Met)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1099G>A (p.Val367Met)

Other names:

NM_000162.5(GCK):c.1099G>A; p.Val367Met

HGVS:

NC_000007.14:g.44145651C>T
NG_008847.2:g.57520G>A
NM_000162.5:c.1099G>AMANE SELECT
NM_001354800.1:c.1099G>A
NM_001354801.1:c.88G>A
NM_001354802.1:c.-42G>A
NM_001354803.2:c.133G>A
NM_033507.3:c.1102G>A
NM_033508.3:c.1096G>A
NP_000153.1:p.Val367Met
NP_001341729.1:p.Val367Met
NP_001341730.1:p.Val30Met
NP_001341732.1:p.Val45Met
NP_277042.1:p.Val368Met
NP_277043.1:p.Val366Met
LRG_1074t1:c.1099G>A
LRG_1074t2:c.1102G>A
LRG_1074:g.57520G>A
LRG_1074p1:p.Val367Met
LRG_1074p2:p.Val368Met
NC_000007.13:g.44185250C>T
NC_000007.13:g.44185250C>T
NM_000162.3:c.1099G>A

Protein change:

V30M

Links:

dbSNP: rs1057521092

NCBI 1000 Genomes Browser:

rs1057521092

Molecular consequence:

NM_001354802.1:c.-42G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000162.5:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.88G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1096G>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
SCV000521045	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 21, 2024)	germline	clinical testing	Citation Link,
SCV002771529	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Aug 16, 2021)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9049484, 10525657, 19934346, 10426385, 21454584, 22771492, 27256595, 26698632, 32375122, 26467025
SCV004295143	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10426385, 10525657, 19934346, 21454584, 26698632, 9049484, 27256595, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000521045

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 21, 2024)

germline

clinical testing

Citation Link,

SCV002771529

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Aug 16, 2021)

unknown

clinical testing

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

SCV004295143

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 28, 2023)

germline

clinical testing

PubMed (8)
[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

Association with nitric oxide synthase on insulin secretory granules regulates glucokinase protein levels.

Markwardt ML, Nkobena A, Ding SY, Rizzo MA.

Mol Endocrinol. 2012 Sep;26(9):1617-29. doi: 10.1210/me.2012-1183. Epub 2012 Jul 6.

PubMed [citation]

PMID:: 22771492
PMCID:: PMC3434526

MODY2 in Asia: analysis of GCK mutations and clinical characteristics.

Zhou Y, Wang S, Wu J, Dong J, Liao L.

Endocr Connect. 2020 May;9(5):471-478. doi: 10.1530/EC-20-0074.

PubMed [citation]

PMID:: 32375122
PMCID:: PMC7274558

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000521045.5

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

Description

Published functional studies demonstrate this impacts posttranslational regulation of GCK (PMID: 19934346, 22771492); Not observed at significant frequency 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 a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 22771492, 21454584, 10426385, 10525657, 19934346, 19790256, 14517946, 15161764, 26698632, 34789923, 37725835, 9049484, 27256595, 36257325, 32375122, 31968686)

#	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 Athena Diagnostics, SCV002771529.1

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

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 suggests this variant results in abnormal protein function. Variant affected interaction with other proteins leading to reduced response to glucose (PMID: 21454584).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004295143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385, 10525657, 19934346, 21454584, 26698632). 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: 381598). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 9049484, 27256595; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 367 of the GCK protein (p.Val367Met).

#	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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