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NM_000162.5(GCK):c.1064T>C (p.Leu355Pro) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 18, 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:
RCV003318506.1

Allele description [Variation Report for NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)]

NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)
Other names:
NM_000162.5(GCK):c.1064T>C; p.Leu355Pro
HGVS:
  • NC_000007.14:g.44145686A>G
  • NG_008847.2:g.57485T>C
  • NM_000162.5:c.1064T>CMANE SELECT
  • NM_001354800.1:c.1064T>C
  • NM_001354801.1:c.53T>C
  • NM_001354802.1:c.-77T>C
  • NM_001354803.2:c.98T>C
  • NM_033507.3:c.1067T>C
  • NM_033508.3:c.1061T>C
  • NP_000153.1:p.Leu355Pro
  • NP_001341729.1:p.Leu355Pro
  • NP_001341730.1:p.Leu18Pro
  • NP_001341732.1:p.Leu33Pro
  • NP_277042.1:p.Leu356Pro
  • NP_277043.1:p.Leu354Pro
  • LRG_1074t1:c.1064T>C
  • LRG_1074t2:c.1067T>C
  • LRG_1074:g.57485T>C
  • LRG_1074p1:p.Leu355Pro
  • LRG_1074p2:p.Leu356Pro
  • NC_000007.13:g.44185285A>G
  • NM_000162.3:c.1064T>C
Protein change:
L18P
Links:
dbSNP: rs1583592156
NCBI 1000 Genomes Browser:
rs1583592156
Molecular consequence:
  • NM_001354802.1:c.-77T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.98T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1067T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1061T>C - 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
SCV004022330ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Uncertain significance
(Jul 18, 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, SCV004022330.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1064T>C variant in the glucokinase gene, GCK, causes an amino acid change of Leucine to Proline at codon 355 (p.(Leu355Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9689, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known DOI:10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor). However, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold. 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 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, the evidence supports the classification of c.1064T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PP2, PP3, PM2_Supporting.

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

Last Updated: May 7, 2024