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.1142T>A (p.Met381Lys)

CA367398767

447383 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8769c01a-ff84-4b3c-91f0-c7f029c0c5e7

HGVS expressions

NM_000162.5:c.1142T>A

NM_000162.5(GCK):c.1142T>A (p.Met381Lys)

NC_000007.14:g.44145608A>T

CM000669.2:g.44145608A>T

NC_000007.13:g.44185207A>T

CM000669.1:g.44185207A>T

NC_000007.12:g.44151732A>T

NG_008847.1:g.48816T>A

NG_008847.2:g.57563T>A

ENST00000395796.8:c.*1140T>A

ENST00000616242.5:c.*262T>A

ENST00000683378.1:n.368T>A

ENST00000336642.9:c.176T>A

ENST00000345378.7:c.1145T>A

ENST00000403799.8:c.1142T>A

ENST00000671824.1:c.1205T>A

ENST00000672743.1:n.154T>A

ENST00000673284.1:c.1142T>A

ENST00000336642.8:n.194T>A

ENST00000345378.6:c.1145T>A

ENST00000395796.7:c.1139T>A

ENST00000403799.7:c.1142T>A

ENST00000437084.1:c.1091T>A

ENST00000459642.1:n.522T>A

ENST00000616242.4:n.1139T>A

NM_000162.3:c.1142T>A

NM_033507.1:c.1145T>A

NM_033508.1:c.1139T>A

NM_000162.4:c.1142T>A

NM_001354800.1:c.1142T>A

NM_001354801.1:c.131T>A

NM_001354802.1:c.2T>A

NM_001354803.1:c.176T>A

NM_033507.2:c.1145T>A

NM_033508.2:c.1139T>A

NM_033507.3:c.1145T>A

NM_033508.3:c.1139T>A

NM_001354803.2:c.176T>A

Likely Pathogenic

PM5 PM3_Supporting PM2_Supporting PP4 PP3 PP2

PS4

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.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 381 (p.(Met381Lys)) 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 0.9459, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant was identified in an individual with neonatal diabetes who was homozygous for this variant (PP4; PM3_Supporting; internal lab contributor). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Lys has an equal or greater Grantham distance (PM5). In summary, c.1142T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4, PM5, PP2, PP3, PM2_Supporting, PM3_Supporting.

PM5

Another missense variant, c.1142T>C (p.Met381Thr), has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Lys has an equal or greater Grantham distance (PM5).

PM3_Supporting

This variant has been detected in an individual with neonatal diabetes who was homozygous for this variant (PM3_Supporting; internal lab contributor).

PM2_Supporting

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

PP4

This variant was identified in in the homozygous state in an individual with neonatal diabetes and negative testing for ABCC8, KCNJ11, and INS (PP4; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9459, 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).

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 (internal lab contributors).

Approved on: 2023-09-09

Published on: 2023-09-09

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