NM_000162.5(GCK):c.1340G>A (p.Arg447Gln) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Feb 8, 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:: RCV000494422.15

Allele description [Variation Report for NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)]

NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)

HGVS:

NC_000007.14:g.44145194C>T
NG_008847.2:g.57977G>A
NM_000162.5:c.1340G>AMANE SELECT
NM_001354800.1:c.1340G>A
NM_001354801.1:c.329G>A
NM_001354802.1:c.200G>A
NM_001354803.2:c.374G>A
NM_033507.3:c.1343G>A
NM_033508.3:c.1337G>A
NP_000153.1:p.Arg447Gln
NP_001341729.1:p.Arg447Gln
NP_001341730.1:p.Arg110Gln
NP_001341731.1:p.Arg67Gln
NP_001341732.1:p.Arg125Gln
NP_277042.1:p.Arg448Gln
NP_277043.1:p.Arg446Gln
LRG_1074t1:c.1340G>A
LRG_1074t2:c.1343G>A
LRG_1074:g.57977G>A
LRG_1074p1:p.Arg447Gln
LRG_1074p2:p.Arg448Gln
NC_000007.13:g.44184793C>T
NM_000162.3:c.1340G>A

Protein change:

R110Q

Links:

dbSNP: rs1131691416

NCBI 1000 Genomes Browser:

rs1131691416

Molecular consequence:

NM_000162.5:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.329G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.374G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1343G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1337G>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
SCV000582084	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 8, 2024)	germline	clinical testing	Citation Link,
SCV002069076	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002771531	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Aug 16, 2022)	unknown	clinical testing	PubMed (17) [See all records that cite these PMIDs] 20337973, 24097065, 28170077, 34440516, 27271189, 28012402, 28701371, 19790256, 24578721, 34023340, 24660669, 33046911, 32533152, 14517956, 22773699, 16965331, 26467025
SCV004295121	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 14517956, 16965331, 20337973, 22773699, 28170077, 34023340, 34440516, 35472491, 36257325, 26587058, 28492532

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

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

Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, Gupta N, Burtt NP, Florez JC, Meigs JB, Taylor H, Lyssenko V, Irgens H, Fox E, Burslem F, Johansson S, Brosnan MJ, Trimmer JK, Newton-Cheh C, Tuomi T, Molven A, Wilson JG, O'Donnell CJ, et al.

Nat Genet. 2013 Nov;45(11):1380-5. doi: 10.1038/ng.2794. Epub 2013 Oct 6.

PubMed [citation]

PMID:: 24097065
PMCID:: PMC4051627

See all PubMed Citations (22)

Details of each submission

From GeneDx, SCV000582084.7

#	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 (gnomAD); In silico analysis supports that this missense variant does not alter 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: 27271189, 19790256, 28012402, 14517946, 14517956, 28170077, 16965331, 22773699, 24097065, 24578721, 33046911, 32533152, 20337973, 34440516, 35472491, 36723869, 36504295, 35737141, 26587058, 36257325)

#	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, SCV002069076.1

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

#	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, SCV002771531.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295121.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 447 of the GCK protein (p.Arg447Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 14517956, 16965331, 20337973, 22773699, 28170077, 34023340, 34440516, 35472491, 36257325). ClinVar contains an entry for this variant (Variation ID: 429500). 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.Arg447 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26587058; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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