NM_000162.5(GCK):c.1372_1373del (p.Lys458fs) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 1, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV003325946.2

Allele description [Variation Report for NM_000162.5(GCK):c.1372_1373del (p.Lys458fs)]

NM_000162.5(GCK):c.1372_1373del (p.Lys458fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1372_1373del (p.Lys458fs)

Other names:

NM_000162.5(GCK):c.1372_1373del; p.Lys458fs

HGVS:

NC_000007.14:g.44145161_44145162del
NG_008847.2:g.58009_58010del
NM_000162.5:c.1372_1373delMANE SELECT
NM_001354800.1:c.1369+3_1369+4del
NM_001354801.1:c.361_362del
NM_001354802.1:c.229+3_229+4del
NM_001354803.2:c.406_407del
NM_033507.3:c.1375_1376del
NM_033508.3:c.1369_1370del
NP_000153.1:p.Lys458fs
NP_001341730.1:p.Lys121fs
NP_001341732.1:p.Lys136fs
NP_277042.1:p.Lys459fs
NP_277043.1:p.Lys457fs
LRG_1074t1:c.1372_1373del
LRG_1074t2:c.1375_1376del
LRG_1074:g.58009_58010del
LRG_1074p1:p.Lys458fs
LRG_1074p2:p.Lys459fs
NC_000007.13:g.44184760_44184761del
NM_000162.3:c.1372_1373delAA
p.Lys458GlufsX8+

Protein change:

K121fs

Links:

dbSNP: rs193922284

NCBI 1000 Genomes Browser:

rs193922284

Molecular consequence:

NM_000162.5:c.1372_1373del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.361_362del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.406_407del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1375_1376del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1369_1370del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1369+3_1369+4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354802.1:c.229+3_229+4del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

Recent activity

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ERBB2 erb-b2 receptor tyrosine kinase 2 [Canis lupus familiaris]
ERBB2 erb-b2 receptor tyrosine kinase 2 [Canis lupus familiaris]
Gene ID:403883

Gene
403883[uid] AND (alive[prop]) (1)
Gene
SSTR2 somatostatin receptor 2 [Sus scrofa]
SSTR2 somatostatin receptor 2 [Sus scrofa]
Gene ID:497059

Gene
497059[uid] AND (alive[prop]) (1)
Gene
RecName: Full=Syntaxin-7
RecName: Full=Syntaxin-7
gi|20532414|sp|O15400.4|STX7_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004032107	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Sep 1, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004032107

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Sep 1, 2023)

germline

curation

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004032107.1

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

Description

The c.1372_1373del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 458 (NM_000162.6), adding 75 novel amino acids before encountering a stop codon (p.(Lys458GlufsTer75)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). Additionally, this variant is absent in gnomAD v.2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes, however PS4 cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant was identified in a case consistent with GCK-hyperglycemia but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). This variant segregated with disease with one informative meiosis in a family with MODY, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID 27236918) (internal lab contributors). In summary, c.1372_1373del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting.

#	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 16, 2023

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