Variant: NM_000162.5(GCK):c.1322C>T (p.Ser441Leu)

CA367397015

435298 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 16ce9b17-deb1-4558-ae14-2bcfa914c103

Approved on: 2023-06-25

Published on: 2023-06-25

HGVS expressions

NM_000162.5:c.1322C>T
NM_000162.5(GCK):c.1322C>T (p.Ser441Leu)
NC_000007.14:g.44145212G>A
CM000669.2:g.44145212G>A
NC_000007.13:g.44184811G>A
CM000669.1:g.44184811G>A
NC_000007.12:g.44151336G>A
NG_008847.1:g.49212C>T
NG_008847.2:g.57959C>T
ENST00000395796.8:c.*1320C>T
ENST00000616242.5:c.*442C>T
ENST00000683378.1:n.548C>T
ENST00000336642.9:c.356C>T
ENST00000345378.7:c.1325C>T
ENST00000403799.8:c.1322C>T
ENST00000671824.1:c.1385C>T
ENST00000672743.1:n.334C>T
ENST00000673284.1:c.1322C>T
ENST00000336642.8:n.374C>T
ENST00000345378.6:c.1325C>T
ENST00000395796.7:c.1319C>T
ENST00000403799.7:c.1322C>T
ENST00000437084.1:c.1271C>T
ENST00000459642.1:n.702C>T
ENST00000616242.4:n.1319C>T
NM_000162.3:c.1322C>T
NM_033507.1:c.1325C>T
NM_033508.1:c.1319C>T
NM_000162.4:c.1322C>T
NM_001354800.1:c.1322C>T
NM_001354801.1:c.311C>T
NM_001354802.1:c.182C>T
NM_001354803.1:c.356C>T
NM_033507.2:c.1325C>T
NM_033508.2:c.1319C>T
NM_033507.3:c.1325C>T
NM_033508.3:c.1319C>T
NM_001354803.2:c.356C>T

Uncertain Significance

• Met criteria codes: PP4 PP3 PP2 PM5_Supporting PM2_Supporting

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1322C>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Leu)) of NM_000162.5. This variant has a non-calculable Popmax filtering allele frequency, with absence in the gnomAD v2.1.1 European non-Finnish population and one copy in the African/African American subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (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). The variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, 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%) (PP4; PMID: 28726111). Another missense variant, c.1322C>G p.(Ser441Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Ser441Leu) (PM5_Supporting). In summary, c.1322C>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, PP3, PP2, PP4, PM5_Supporting.

Met criteria codes

• PP4: 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%) (PP4; PMID: 28726111)
• PP3: Variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than 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).
• PM5_Supporting: Another missense variant, c.1322C>G p.(Ser441Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Ser441Leu) (PM5_Supporting).
• PM2_Supporting: This variant has a non-calculable Popmax filtering allele frequency, with absence in the gnomAD v2.1.1 European non-Finnish population and one copy in the African/African American subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).