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NM_000162.5(GCK):c.1129C>A (p.Arg377Ser) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 20, 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:
RCV003330331.1

Allele description [Variation Report for NM_000162.5(GCK):c.1129C>A (p.Arg377Ser)]

NM_000162.5(GCK):c.1129C>A (p.Arg377Ser)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1129C>A (p.Arg377Ser)
Other names:
NM_000162.5(GCK):c.1129C>A; p.Arg377Ser
HGVS:
  • NC_000007.14:g.44145621G>T
  • NG_008847.2:g.57550C>A
  • NM_000162.5:c.1129C>AMANE SELECT
  • NM_001354800.1:c.1129C>A
  • NM_001354801.1:c.118C>A
  • NM_001354802.1:c.-12C>A
  • NM_001354803.2:c.163C>A
  • NM_033507.3:c.1132C>A
  • NM_033508.3:c.1126C>A
  • NP_000153.1:p.Arg377Ser
  • NP_001341729.1:p.Arg377Ser
  • NP_001341730.1:p.Arg40Ser
  • NP_001341732.1:p.Arg55Ser
  • NP_277042.1:p.Arg378Ser
  • NP_277043.1:p.Arg376Ser
  • LRG_1074t1:c.1129C>A
  • LRG_1074t2:c.1132C>A
  • LRG_1074:g.57550C>A
  • LRG_1074p1:p.Arg377Ser
  • LRG_1074p2:p.Arg378Ser
  • NC_000007.13:g.44185220G>T
  • NM_000162.3:c.1129C>A
Protein change:
R376S
Molecular consequence:
  • NM_001354802.1:c.-12C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1129C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1129C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.118C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.163C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1132C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1126C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004037459ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Likely pathogenic
(Sep 20, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004037459.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1129C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 377 (p.(Arg377Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in a family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). Another missense variant, c.1129C>T p.Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377Ser) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Moderate, PM5_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024