VCV000450262.5 - ClinVar

NM_000162.5(GCK):c.762T>A (p.Asn254Lys)

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
Likely pathogenic(2); Uncertain risk allele(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.762T>A (p.Asn254Lys)

Variation ID: 450262 Accession: VCV000450262.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44147751 (GRCh38) [ NCBI UCSC ] 7: 44187350 (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	Dec 19, 2017	Feb 28, 2024	Jun 24, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.762T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Asn254Lys	missense
NM_001354800.1:c.762T>A	NP_001341729.1:p.Asn254Lys	missense
NM_033507.3:c.765T>A	NP_277042.1:p.Asn255Lys	missense
NM_033508.3:c.759T>A	NP_277043.1:p.Asn253Lys	missense
NC_000007.14:g.44147751A>T
NC_000007.13:g.44187350A>T
NG_008847.2:g.55420T>A
LRG_1074:g.55420T>A
LRG_1074t1:c.762T>A	LRG_1074p1:p.Asn254Lys
LRG_1074t2:c.765T>A	LRG_1074p2:p.Asn255Lys

... more HGVS ... less HGVS

Protein change

N254K, N255K, N253K

Other names

Canonical SPDI

NC_000007.14:44147750:A:T

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: CA367400611 dbSNP: rs1554335141 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	1093	1119

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.
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 24, 2022	RCV000521168.4
Maturity onset diabetes mellitus in young	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV002463716.1

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.
Likely pathogenic (Jun 29, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618819.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: The N254K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant … (more) The N254K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N254K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (N254H) and in nearby residues (M251V/K/T/I, C252G/R/S/Y, V253L/F/A, T255A/I/S, E256K/D, W257R) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
Uncertain 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: SCV002605104.1 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 rs1554335141 in MODY, yet. (less)
Likely pathogenic (Jun 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002977987.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 26587058 Comment: This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (Invitae). In summary, the currently available evidence … (more) This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn254 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26587058). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 450262). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 254 of the GCK protein (p.Asn254Lys). (less)

Comment:

The N254K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N254K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (N254H) and in nearby residues (M251V/K/T/I, C252G/R/S/Y, V253L/F/A, T255A/I/S, E256K/D, W257R) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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 rs1554335141 in MODY, yet.

Comment:

This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn254 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26587058). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 450262). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 254 of the GCK protein (p.Asn254Lys).

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
A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins.	Esquiaveto-Aun AM	Diabetology & metabolic syndrome	2015	PMID: 26587058

Text-mined citations for rs1554335141 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.762T>A (p.Asn254Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554335141 ...