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]

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Variant: NM_000162.5(GCK):c.203G>A (p.Gly68Asp)

CA157919943

972774 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 6458de25-66b8-404a-ae4e-b313b3209984

HGVS expressions

NM_000162.5:c.203G>A

NM_000162.5(GCK):c.203G>A (p.Gly68Asp)

NC_000007.14:g.44153306C>T

CM000669.2:g.44153306C>T

NC_000007.13:g.44192905C>T

CM000669.1:g.44192905C>T

NC_000007.12:g.44159430C>T

NG_008847.1:g.41118G>A

NG_008847.2:g.49865G>A

ENST00000395796.8:c.*201G>A

ENST00000616242.5:c.203G>A

ENST00000682635.1:n.689G>A

ENST00000345378.7:c.206G>A

ENST00000403799.8:c.203G>A

ENST00000671824.1:c.203G>A

ENST00000673284.1:c.203G>A

ENST00000345378.6:c.206G>A

ENST00000395796.7:c.200G>A

ENST00000403799.7:c.203G>A

ENST00000437084.1:c.203G>A

ENST00000616242.4:c.200G>A

NM_000162.3:c.203G>A

NM_033507.1:c.206G>A

NM_033508.1:c.200G>A

NM_000162.4:c.203G>A

NM_001354800.1:c.203G>A

NM_033507.2:c.206G>A

NM_033508.2:c.200G>A

NM_033507.3:c.206G>A

NM_033508.3:c.200G>A

Likely Benign

BS2 BP2 BS3_Supporting PP3 PP2

BS1 PS4 PP4 PM2

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.203G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 68 (p.(Gly68Asp)) 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 0.9829, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). However, functional studies demonstrated the p.Gly68Asp protein has no impact on function, with a relative activity index (RAI) > 0.5, a relative stability index (RSI) >0.5 and normal GKRP IC50 and GKA fold activation (BS3_Supporting; PMIDs: 25015100, 22611063). The Popmax filtering allele frequency of the c.203G>A variant in gnomAD v2.1.1 is 0.00001123, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in at least 6 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 26611063, PMID: 30191644, PMID: 25555642, PMID: 33046911, internal lab contributors). This variant was identified in an individual with a clinical history suggestive GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributor). However, the variant was identified in an individual with a normal fasting glucose (BS2; PMIDs: 23799006, 22611063). Lastly, this variant has been observed in an individual who had GCK-hyperglycemia and not permanent neonatal diabetes in trans with the variant c.128G>A, p.Arg43His (PMID: 22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). In summary, c.203G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version1.3.0, approved 8/11/2023): BS2, BS3_Supporting, BP2, PP2, PP3.

BS2

This variant was identified in an individual with a normal fasting glucose (BS2; PMIDs: 23799006, 22611063).

BP2

This variant has been observed in an individual who had GCK-hyperglycemia and not permanent neonatal diabetes in trans with the variant c.128G>A, p.Arg43His (PMID: 22611063), which is classified as pathogenic by the ClinGen MDEP (BP2).

BS3_Supporting

Functional studies demonstrated the p.Gly68Asp protein has no impact on function, with a relative activity index (RAI) > 0.5, a relative stability index (RSI) >0.5 and normal GKRP IC50 and GKA fold activation (BS3_Supporting; PMIDs: 25015100, 22611063).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9829, 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).

BS1

The Popmax filtering allele frequency of the c.203G>A variant in gnomAD v2.1.1 is 0.00001123, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

PS4

This variant was identified in at least 6 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 22611063, PMID: 30191644, PMID: 25555642, PMID: 33046911, internal lab contributors).

PP4

This variant was identified in an individual with a clinical history suggestive GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributor).

PM2

Approved on: 2023-12-08

Published on: 2023-12-08

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