VCV002571655.1 - ClinVar

NM_000162.5(GCK):c.1378del (p.Ala460fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

1 submission

1 submitter

1 condition

Reviewed by expert panel

Pathogenic

Jun 2023 by ClinGen Monoge… FDA Recognized Database

for Maturity-onset diabetes of the young type 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000162.5(GCK):c.1378del (p.Ala460fs)

Variation ID: 2571655 Accession: VCV002571655.1

Type and length

Deletion, 1 bp

Location

Cytogenetic: 7p13 7: 44145156 (GRCh38) [ NCBI UCSC ] 7: 44184755 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 17, 2023	Jul 16, 2023	Jun 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.1378del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Ala460fs	frameshift
NM_001354800.1:c.1369+9del		intron variant
NM_001354801.1:c.367del	NP_001341730.1:p.Ala123fs	frameshift
NM_001354802.1:c.229+9del		intron variant
NM_001354803.2:c.412del	NP_001341732.1:p.Ala138fs	frameshift
NM_033507.3:c.1381del	NP_277042.1:p.Ala461fs	frameshift
NM_033508.3:c.1375del	NP_277043.1:p.Ala459fs	frameshift
NC_000007.14:g.44145157del
NC_000007.13:g.44184756del
NG_008847.2:g.58015del
LRG_1074:g.58015del
LRG_1074t1:c.1378del	LRG_1074p1:p.Ala460fs
LRG_1074t2:c.1381del	LRG_1074p2:p.Ala461fs

... more HGVS ... less HGVS

Protein change

A123fs, A138fs, A459fs, A460fs, A461fs

Other names

NM_001354803.2:c.412del

Canonical SPDI

NC_000007.14:44145155:CC:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GCK		-	-	GRCh38 GRCh37	1091	1117

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Maturity-onset diabetes of the young type 2	Pathogenic (1)	reviewed by expert panel	Jun 18, 2023	RCV003313365.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 18, 2023)	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0) Method: curation	Maturity-onset diabetes of the young type 2 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Monogenic Diabetes Variant Curation Expert Panel FDA Recognized Database Accession: SCV004012140.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/44ebdc11-ff37-4204-814b-b927afcb97ea Comment: The c.1378del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), adding 154 novel amino acids before encountering … (more) The c.1378del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), adding 154 novel amino acids before encountering a stop codon (p.(Ala460ProfsTer154)). 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). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 15841481). In summary, c.1378del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4_Moderate. (less)

Comment:

The c.1378del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), adding 154 novel amino acids before encountering a stop codon (p.(Ala460ProfsTer154)). 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). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 15841481). In summary, c.1378del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4_Moderate.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/44ebdc11-ff37-4204-814b-b927afcb97ea	-	-	-	-

Text-mined citations for this variant ...

Record last updated Jul 29, 2023

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.1378del (p.Ala460fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...