VCV000435305.9 - ClinVar

NM_000162.5(GCK):c.941T>C (p.Leu314Pro)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely risk allele(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000162.5(GCK):c.941T>C (p.Leu314Pro)

Variation ID: 435305 Accession: VCV000435305.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44146541 (GRCh38) [ NCBI UCSC ] 7: 44186140 (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	Aug 28, 2017	May 1, 2024	Mar 22, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.941T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Leu314Pro	missense
NM_001354800.1:c.941T>C	NP_001341729.1:p.Leu314Pro	missense
NM_001354801.1:c.8+78T>C		intron variant
NM_033507.3:c.944T>C	NP_277042.1:p.Leu315Pro	missense
NM_033508.3:c.938T>C	NP_277043.1:p.Leu313Pro	missense
NC_000007.14:g.44146541A>G
NC_000007.13:g.44186140A>G
NG_008847.2:g.56630T>C
LRG_1074:g.56630T>C
LRG_1074t1:c.941T>C	LRG_1074p1:p.Leu314Pro
LRG_1074t2:c.944T>C	LRG_1074p2:p.Leu315Pro

... more HGVS ... less HGVS

Protein change

L314P, L315P, L313P

Other names

Canonical SPDI

NC_000007.14:44146540:A:G

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

ClinGen: CA367399950 dbSNP: rs1554334886 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)	criteria provided, single submitter	Feb 1, 2016	RCV000500565.6
Maturity onset diabetes mellitus in young	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 22, 2019	RCV002376921.4

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 (Feb 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MODY, type II Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594958.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Likely risk allele (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Maturity onset diabetes mellitus in young (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002605122.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Publications: PubMed (6) PubMed: 33129248‚ 27269892‚ 32375122‚ 31197960‚ 30257192‚ 29510678 Comment: Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet … (more) Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554334886 in MODY, yet. (less)
Uncertain significance (Mar 22, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Maturity onset diabetes mellitus in young Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002685023.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 18248649 Comment: The p.L314P variant (also known as c.941T>C), located in coding exon 8 of the GCK gene, results from a T to C substitution at nucleotide … (more) The p.L314P variant (also known as c.941T>C), located in coding exon 8 of the GCK gene, results from a T to C substitution at nucleotide position 941. The leucine at codon 314 is replaced by proline, an amino acid with similar properties. This variant was identified in one individual with a clinical diagnosis of maturity-onset diabetes of the young (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. (less)

Comment:

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554334886 in MODY, yet.

Comment:

The p.L314P variant (also known as c.941T>C), located in coding exon 8 of the GCK gene, results from a T to C substitution at nucleotide position 941. The leucine at codon 314 is replaced by proline, an amino acid with similar properties. This variant was identified in one individual with a clinical diagnosis of maturity-onset diabetes of the young (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

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
Clinical implications of the glucokinase impaired function - GCK MODY today.	Hulín J	Physiological research	2020	PMID: 33129248
MODY2 in Asia: analysis of GCK mutations and clinical characteristics.	Zhou Y	Endocrine connections	2020	PMID: 32375122
Association of a homozygous GCK missense mutation with mild diabetes.	Marucci A	Molecular genetics & genomic medicine	2019	PMID: 31197960
Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients.	Liu L	Metabolism: clinical and experimental	2018	PMID: 30257192
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY).	Li X	BMC pediatrics	2018	PMID: 29510678
GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature.	Ping Xiao Y	Journal of pediatric endocrinology & metabolism : JPEM	2016	PMID: 27269892
Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients.	Garin I	Clinical endocrinology	2008	PMID: 18248649

Text-mined citations for rs1554334886 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.941T>C (p.Leu314Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554334886 ...