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.1024A>C (p.Thr342Pro)

CA157913750

908615 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 29f5347b-abc0-44ae-bbf6-c5464d91d0b5

HGVS expressions

NM_000162.5:c.1024A>C

NM_000162.5(GCK):c.1024A>C (p.Thr342Pro)

NC_000007.14:g.44145726T>G

CM000669.2:g.44145726T>G

NC_000007.13:g.44185325T>G

CM000669.1:g.44185325T>G

NC_000007.12:g.44151850T>G

NG_008847.1:g.48698A>C

NG_008847.2:g.57445A>C

ENST00000395796.8:c.*1022A>C

ENST00000616242.5:c.*144A>C

ENST00000683378.1:n.250A>C

ENST00000336642.9:c.58A>C

ENST00000345378.7:c.1027A>C

ENST00000403799.8:c.1024A>C

ENST00000671824.1:c.1087A>C

ENST00000672743.1:n.36A>C

ENST00000673284.1:c.1024A>C

ENST00000336642.8:c.76A>C

ENST00000345378.6:c.1027A>C

ENST00000395796.7:c.1021A>C

ENST00000403799.7:c.1024A>C

ENST00000437084.1:c.973A>C

ENST00000459642.1:n.404A>C

ENST00000473353.1:n.322A>C

ENST00000616242.4:c.1021A>C

NM_000162.3:c.1024A>C

NM_033507.1:c.1027A>C

NM_033508.1:c.1021A>C

NM_000162.4:c.1024A>C

NM_001354800.1:c.1024A>C

NM_001354801.1:c.13A>C

NM_001354802.1:c.-117A>C

NM_001354803.1:c.58A>C

NM_033507.2:c.1027A>C

NM_033508.2:c.1021A>C

NM_033507.3:c.1027A>C

NM_033508.3:c.1021A>C

NM_001354803.2:c.58A>C

Benign

BS4 BS2 PP2

PM2 PM5 BS3 BS1 PS4 PP3

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.1024A>C variant in the glucokinase gene, GCK, causes an amino acid change of threonine to proline at codon 342 (p.(Thr342Pro)) 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 has a Popmax filtering allele frequency of 0.000004789, which is between the MDEP thresholds for PM2_Supporting and BS1. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21604084, PMID: 33046911). However, this variant was identified in multiple individuals with a normal fasting glucose (BS2; PMID: 23799006, PMID 21604084). Additionally, this variant does not segregate with diabetes in one family in the literature (BS4; PMID: 21604084). This variant has a REVEL score of 0.296, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. Additionally, functional studies are inconclusive on whether the p.Thr342Pro variant impacts glucokinase function (normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA interaction) (PMID 25015100). Two other missense variants, c.1024A>T (p.Thr342Ser) and c.1025C>T p.Thr342Met have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, the c.1024A>C variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BS4, PP2.

BS4

This variant does not segregate with diabetes in one family in the literature (BS4; PMID 21604084).

BS2

This variant was identified in multiple individuals with a normal fasting glucose (BS2; PMID: 23799006, PMID 21604084).

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).

PM2

This variant has a Popmax filtering allele frequency of 0.000004789, which is between the MDEP thresholds for PM2_Supporting and BS1.

PM5

Two other missense variants, c.1024A>T (p.Thr342Ser) and c.1025C>T p.Thr342Met have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

BS3

Functional studies are inconclusive on whether the p.Thr342Pro variant impacts glucokinase function (normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA interaction) (PMID 25015100).

BS1

This variant has a Popmax filtering allele frequency of 0.000004789, which is between the MDEP thresholds for PM2_Supporting and BS1.

PS4

This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21604084, PMID: 33046911).

PP3

This variant has a REVEL score of 0.296, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function.

Approved on: 2024-02-02

Published on: 2024-02-02

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