VCV001700675.3 - ClinVar

NM_000162.5(GCK):c.1264C>T (p.Arg422Trp)

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.

(2)

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(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.1264C>T (p.Arg422Trp)

Variation ID: 1700675 Accession: VCV001700675.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44145270 (GRCh38) [ NCBI UCSC ] 7: 44184869 (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	Oct 1, 2022	May 1, 2024	Aug 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.1264C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Arg422Trp	missense
NM_000162.3:c.1264C>T
NM_001354800.1:c.1264C>T	NP_001341729.1:p.Arg422Trp	missense
NM_001354801.1:c.253C>T	NP_001341730.1:p.Arg85Trp	missense
NM_001354802.1:c.124C>T	NP_001341731.1:p.Arg42Trp	missense
NM_001354803.2:c.298C>T	NP_001341732.1:p.Arg100Trp	missense
NM_033507.3:c.1267C>T	NP_277042.1:p.Arg423Trp	missense
NM_033508.3:c.1261C>T	NP_277043.1:p.Arg421Trp	missense
NC_000007.14:g.44145270G>A
NC_000007.13:g.44184869G>A
NG_008847.2:g.57901C>T
LRG_1074:g.57901C>T
LRG_1074t1:c.1264C>T	LRG_1074p1:p.Arg422Trp
LRG_1074t2:c.1267C>T	LRG_1074p2:p.Arg423Trp

... more HGVS ... less HGVS

Protein change

R100W, R421W, R422W, R423W, R42W, R85W

Other names

Canonical SPDI

NC_000007.14:44145269:G:A

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	1096	1122

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 mellitus in young	Uncertain significance (1)	criteria provided, single submitter	Jun 20, 2019	RCV002443287.2
Maturity-onset diabetes of the young type 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 2, 2022	RCV002285553.2

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 (Aug 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Maturity-onset diabetes of the young type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Geisinger Clinic, Geisinger Health System Accession: SCV002562155.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 36257325 Comment: PM2, PP3, PP4, PS4_Supporting, PP1, PP2, PM5_Supporting Number of individuals with the variant: 3
Uncertain significance (Jun 20, 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: SCV002676302.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 23771925 Comment: The p.R422W variant (also known as c.1264C>T), located in coding exon 10 of the GCK gene, results from a C to T substitution at nucleotide … (more) The p.R422W variant (also known as c.1264C>T), located in coding exon 10 of the GCK gene, results from a C to T substitution at nucleotide position 1264. The arginine at codon 422 is replaced by tryptophan, an amino acid with dissimilar properties. Another variant affecting this codon (p.R422L, c.1265G>T) has been detected in a cohort of patients with suspected maturity onset diabetes of the young (Pihoker C et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:4055-62). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The p.R422W variant (also known as c.1264C>T), located in coding exon 10 of the GCK gene, results from a C to T substitution at nucleotide position 1264. The arginine at codon 422 is replaced by tryptophan, an amino acid with dissimilar properties. Another variant affecting this codon (p.R422L, c.1265G>T) has been detected in a cohort of patients with suspected maturity onset diabetes of the young (Pihoker C et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:4055-62). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.	Mirshahi UL	American journal of human genetics	2022	PMID: 36257325
Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.	Pihoker C	The Journal of clinical endocrinology and metabolism	2013	PMID: 23771925

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.1264C>T (p.Arg422Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...