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.483G>A (p.Lys161=)

CA213792

36224 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 836b2fb2-08d5-4310-9231-f5c705113857

HGVS expressions

NM_000162.5:c.483G>A

NM_000162.5(GCK):c.483G>A (p.Lys161=)

NC_000007.14:g.44150956C>T

CM000669.2:g.44150956C>T

NC_000007.13:g.44190555C>T

CM000669.1:g.44190555C>T

NC_000007.12:g.44157080C>T

NG_008847.1:g.43468G>A

NG_008847.2:g.52215G>A

ENST00000395796.8:c.*481G>A

ENST00000616242.5:c.483G>A

ENST00000682635.1:n.969G>A

ENST00000345378.7:c.486G>A

ENST00000403799.8:c.483G>A

ENST00000671824.1:c.483G>A

ENST00000673284.1:c.483G>A

ENST00000345378.6:c.486G>A

ENST00000395796.7:c.480G>A

ENST00000403799.7:c.483G>A

ENST00000437084.1:c.432G>A

ENST00000616242.4:n.480G>A

NM_000162.3:c.483G>A

NM_033507.1:c.486G>A

NM_033508.1:c.480G>A

NM_000162.4:c.483G>A

NM_001354800.1:c.483G>A

NM_033507.2:c.486G>A

NM_033508.2:c.480G>A

NM_033507.3:c.486G>A

NM_033508.3:c.480G>A

Pathogenic

PM2_Supporting PP1_Strong PS4_Moderate PP3 PS3

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 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.483G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 161 (p.(Lys161=)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.85 for donor gain and 0.52 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3), and there is evidence from RNA studies that this variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor). This variant was identified in five unrelated individuals with mildly elevated HbA1c that did not require treatment, and segregated with the phenotype, with four informative meioses in three families (PS4_Moderate, PP1_Strong; PMID: 1956454, Internal lab contributors). In summary, c.483G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 3/23/23): PM2_Supporting, PP3, PS4_Moderate, PP1_Strong, PS3.

PM2_Supporting

This variant is absent from gnomAD v2.1.1.

PP1_Strong

Variant segregated with mildly elevated HbA1c, with four informative meioses in three families

PS4_Moderate

This variant was identified in five unrelated individuals with mildly elevated HbA1c that did not require treatment.

PP3

It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.85 for donor gain and 0.52 for donor loss, which are greater than the MDEP cutoff of 0.2)

PS3

There is evidence from RNA studies that this variant results in aberrant splicing, indicating that this variant impacts protein function (Internal lab contributor).

Approved on: 2023-05-26

Published on: 2023-05-26

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.