NM_000162.5(GCK):c.1155del (p.Leu386fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 3, 2023
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:: RCV000598690.7

Allele description [Variation Report for NM_000162.5(GCK):c.1155del (p.Leu386fs)]

NM_000162.5(GCK):c.1155del (p.Leu386fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1155del (p.Leu386fs)

HGVS:

NC_000007.14:g.44145598del
NG_008847.2:g.57576del
NM_000162.5:c.1155delMANE SELECT
NM_001354800.1:c.1155del
NM_001354801.1:c.144del
NM_001354802.1:c.15del
NM_001354803.2:c.189del
NM_033507.3:c.1158del
NM_033508.3:c.1152del
NP_000153.1:p.Leu386fs
NP_001341729.1:p.Leu386fs
NP_001341730.1:p.Leu49fs
NP_001341731.1:p.Leu6fs
NP_001341732.1:p.Leu64fs
NP_277042.1:p.Leu387fs
NP_277043.1:p.Leu385fs
LRG_1074t1:c.1155del
LRG_1074t2:c.1158del
LRG_1074:g.57576del
LRG_1074p1:p.Leu386fs
LRG_1074p2:p.Leu387fs
NC_000007.13:g.44185194del
NC_000007.13:g.44185197del
NM_000162.3:c.1155del
NM_000162.3:c.1155delG

Protein change:

L385fs

Links:

dbSNP: rs1400535021

NCBI 1000 Genomes Browser:

rs1400535021

Molecular consequence:

NM_000162.5:c.1155del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1155del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.144del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.15del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.189del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1158del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1152del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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RecName: Full=Nuclear transcription factor Y subunit alpha; AltName: Full=CAAT b...
RecName: Full=Nuclear transcription factor Y subunit alpha; AltName: Full=CAAT box DNA-binding protein subunit A; AltName: Full=Nuclear transcription factor Y subunit A; Short=NF-YA
gi|115844|sp|P23511.2|NFYA_HUMAN

Protein
Chain E, Cytochrome c oxidase subunit 5A, mitochondrial
Chain E, Cytochrome c oxidase subunit 5A, mitochondrial
gi|635576114|pdb|3WG7|E

Protein
vx12e05.x1 Soares_thymus_2NbMT Mus musculus cDNA clone IMAGE:1264256 3', mRNA se...
vx12e05.x1 Soares_thymus_2NbMT Mus musculus cDNA clone IMAGE:1264256 3', mRNA sequence
gi|4482732|gnl|dbEST|2366533|gb|AI5 .1|

Nucleotide
Cricetulus griseus ceramide transporter 1 (Cert1), mRNA
Cricetulus griseus ceramide transporter 1 (Cert1), mRNA
gi|345842356|ref|NM_001244026.1|

Nucleotide
Mus musculus RIKEN cDNA 6530401D17 gene, mRNA (cDNA clone IMAGE:4502106)
Mus musculus RIKEN cDNA 6530401D17 gene, mRNA (cDNA clone IMAGE:4502106)
gi|16740808|gb|BC016270.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000709947	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (May 11, 2020)	germline	clinical testing	Citation Link,
SCV004295137	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 3, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7553875, 9867845, 14578306, 24323243, 25015100, 23771925, 32533152, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000709947

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(May 11, 2020)

germline

clinical testing

Citation Link,

SCV004295137

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 3, 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

Citations

PubMed

Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis.

Grupe A, Hultgren B, Ryan A, Ma YH, Bauer M, Stewart TA.

Cell. 1995 Oct 6;83(1):69-78.

PubMed [citation]

PMID:: 7553875

Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.

Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA.

J Biol Chem. 1999 Jan 1;274(1):305-15.

PubMed [citation]

PMID:: 9867845

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000709947.4

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

Description

Frameshift variant predicted to result in protein truncation, as the last 80 amino acids are replaced with 15 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23771925)

#	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, SCV004295137.1

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

Description

This sequence change creates a premature translational stop signal (p.Leu386Trpfs*16) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is present in population databases (no rsID available, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 23771925, 32533152). ClinVar contains an entry for this variant (Variation ID: 503699). 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 8, 2024

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