NM_000162.5(GCK):c.944T>A (p.Leu315His) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 2, 2022
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:: RCV001818187.7

Allele description [Variation Report for NM_000162.5(GCK):c.944T>A (p.Leu315His)]

NM_000162.5(GCK):c.944T>A (p.Leu315His)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.944T>A (p.Leu315His)

HGVS:

NC_000007.14:g.44146538A>T
NG_008847.2:g.56633T>A
NM_000162.5:c.944T>AMANE SELECT
NM_001354800.1:c.944T>A
NM_001354801.1:c.8+81T>A
NM_033507.3:c.947T>A
NM_033508.3:c.941T>A
NP_000153.1:p.Leu315His
NP_001341729.1:p.Leu315His
NP_277042.1:p.Leu316His
NP_277043.1:p.Leu314His
LRG_1074t1:c.944T>A
LRG_1074t2:c.947T>A
LRG_1074:g.56633T>A
LRG_1074p1:p.Leu315His
LRG_1074p2:p.Leu316His
NC_000007.13:g.44186137A>T
NM_000162.3:c.944T>A

Protein change:

L314H

Links:

dbSNP: rs193922338

NCBI 1000 Genomes Browser:

rs193922338

Molecular consequence:

NM_001354801.1:c.8+81T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000162.5:c.944T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.944T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.947T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.941T>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
SCV002067347	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003439944	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16602010, 17204055, 22332836, 26552609, 22493702, 26208450, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002067347

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 11, 2019)

germline

clinical testing

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

SCV003439944

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 2, 2022)

germline

clinical testing

PubMed (7)
[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

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

Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents.

Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, Cerná M, Pedersen O, Hansen T.

Eur J Pediatr. 2006 Jul;165(7):446-52. Epub 2006 Apr 7.

PubMed [citation]

PMID:: 16602010

See all PubMed Citations (8)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002067347.1

#	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.944T>A, in exon 8 that results in an amino acid change, p.Leu315His. This sequence change has been previously described in patients with GCK-related MODY in multiple unrelated family members and is one of the one of the most prevalent GCK mutations in the Czech population (PMIDs: 20337973, 22332836, 17204055). The p.Leu315His change affects a highly conserved amino acid residue located in a functional domain of the GCK protein that is known to be functional and other pathogenic variants have been described in this region. The p.Leu315His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies for this sequence change showed a severe loss of glucokinase activity (PMID: 26208450).

#	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, SCV003439944.2

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

Description

ClinVar contains an entry for this variant (Variation ID: 36266). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 16602010, 17204055, 22332836, 26552609). 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 leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 315 of the GCK protein (p.Leu315His). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 22493702, 26208450).

#	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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