NM_000162.5(GCK):c.1087G>A (p.Asp363Asn) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 19, 2023
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:: RCV000479890.10

Allele description [Variation Report for NM_000162.5(GCK):c.1087G>A (p.Asp363Asn)]

NM_000162.5(GCK):c.1087G>A (p.Asp363Asn)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1087G>A (p.Asp363Asn)

Other names:

NM_000162.5(GCK):c.1087G>A; p.Asp363Asn

HGVS:

NC_000007.14:g.44145663C>T
NG_008847.2:g.57508G>A
NM_000162.5:c.1087G>AMANE SELECT
NM_001354800.1:c.1087G>A
NM_001354801.1:c.76G>A
NM_001354802.1:c.-54G>A
NM_001354803.2:c.121G>A
NM_033507.3:c.1090G>A
NM_033508.3:c.1084G>A
NP_000153.1:p.Asp363Asn
NP_001341729.1:p.Asp363Asn
NP_001341730.1:p.Asp26Asn
NP_001341732.1:p.Asp41Asn
NP_277042.1:p.Asp364Asn
NP_277043.1:p.Asp362Asn
LRG_1074t1:c.1087G>A
LRG_1074t2:c.1090G>A
LRG_1074:g.57508G>A
LRG_1074p1:p.Asp363Asn
LRG_1074p2:p.Asp364Asn
NC_000007.13:g.44185262C>T
NM_000162.3:c.1087G>A

Protein change:

D26N

Links:

dbSNP: rs1064793134

NCBI 1000 Genomes Browser:

rs1064793134

Molecular consequence:

NM_001354802.1:c.-54G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000162.5:c.1087G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1087G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.76G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.121G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1090G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1084G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Cited in PMC for PubMed (Select 28761823) (2)
PMC
RING-H2 finger protein ATL80 [Triticum urartu]
RING-H2 finger protein ATL80 [Triticum urartu]
gi|474447232|gb|EMS68646.1||gnl|WGS |TRIUR3_20769

Protein
Pseudoloma neurophilia strain MK1 NODE_9540, whole genome shotgun sequence
Pseudoloma neurophilia strain MK1 NODE_9540, whole genome shotgun sequence
gi|948276713|gb|LGUB01001096.1||gnl LGUB01|NODE_9540

Nucleotide
Pseudoloma neurophilia strain MK1 NODE_9970, whole genome shotgun sequence
Pseudoloma neurophilia strain MK1 NODE_9970, whole genome shotgun sequence
gi|948276653|gb|LGUB01001123.1||gnl LGUB01|NODE_9970

Nucleotide
Pseudoloma neurophilia strain MK1 NODE_10388, whole genome shotgun sequence
Pseudoloma neurophilia strain MK1 NODE_10388, whole genome shotgun sequence
gi|948276605|gb|LGUB01001145.1||gnl LGUB01|NODE_10388

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565032	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 25, 2021)	germline	clinical testing	Citation Link,
SCV002067393	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002771543	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Jun 19, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19790256, 32041611, 36257325, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000565032

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 25, 2021)

germline

clinical testing

Citation Link,

SCV002067393

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 31, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002771543

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Jun 19, 2023)

unknown

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 (5)

Details of each submission

From GeneDx, SCV000565032.4

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

Description

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19790256, 32041611)

#	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 Genetic Services Laboratory, University of Chicago, SCV002067393.1

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

Description

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1087G>A, in exon 9 that results in an amino acid change, p.Asp363Asn. The p.Asp363Asn change affects a highly conserved amino acid residue located in domain of the GCK protein that is known to be functional. The p.Asp363Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, MutationTaster, REVEL). This is a novel sequence change that is not present in the large population databases (ExAC and gnomAD). This particular amino acid change has been reported in association with maturity onset diabetes of the young (MODY) but no additional information regarding the clinical presentation or functional studies was provided (PMID: 19790256). Additionally, this group also reported a different missense variant, c.1088A>T(p.Asp363Val), affecting the same amino acid residue in a different family with MODY. Furthermore, the p.Asp363Asn amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in patients with GCK-MODY. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.

#	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, SCV002771543.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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

Last Updated: May 7, 2024

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