Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000162.5(GCK):c.1181G>T (p.Arg394Leu)

CA367398578

1522625 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7b717baa-5df4-4bbc-8132-edfcceb7b495

HGVS expressions

NM_000162.5:c.1181G>T

NM_000162.5(GCK):c.1181G>T (p.Arg394Leu)

NC_000007.14:g.44145569C>A

CM000669.2:g.44145569C>A

NC_000007.13:g.44185168C>A

CM000669.1:g.44185168C>A

NC_000007.12:g.44151693C>A

NG_008847.1:g.48855G>T

NG_008847.2:g.57602G>T

ENST00000395796.8:c.*1179G>T

ENST00000616242.5:c.*301G>T

ENST00000683378.1:n.407G>T

ENST00000336642.9:c.215G>T

ENST00000345378.7:c.1184G>T

ENST00000403799.8:c.1181G>T

ENST00000671824.1:c.1244G>T

ENST00000672743.1:n.193G>T

ENST00000673284.1:c.1181G>T

ENST00000336642.8:n.233G>T

ENST00000345378.6:c.1184G>T

ENST00000395796.7:c.1178G>T

ENST00000403799.7:c.1181G>T

ENST00000437084.1:c.1130G>T

ENST00000459642.1:n.561G>T

ENST00000616242.4:n.1178G>T

NM_000162.3:c.1181G>T

NM_033507.1:c.1184G>T

NM_033508.1:c.1178G>T

NM_000162.4:c.1181G>T

NM_001354800.1:c.1181G>T

NM_001354801.1:c.170G>T

NM_001354802.1:c.41G>T

NM_001354803.1:c.215G>T

NM_033507.2:c.1184G>T

NM_033508.2:c.1178G>T

NM_033507.3:c.1184G>T

NM_033508.3:c.1178G>T

NM_001354803.2:c.215G>T

Uncertain Significance

PP3 PP2 PP4_Moderate PM2_Supporting

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1181G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 394 (p.(Arg394Leu)) of transcript NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 three generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). In summary, c.1181G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.801, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3).

PP2

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).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and three generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Approved on: 2023-07-16

Published on: 2023-07-16

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