Variant: NM_001354803.2:c.347T>A

CA367397060

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 8beea8ae-86e4-42ba-a1d2-347e63f8e418

Approved on: 2023-06-20

Published on: 2023-06-20

HGVS expressions

NM_001354803.2:c.347T>A
NC_000007.14:g.44145221A>T
CM000669.2:g.44145221A>T
NC_000007.13:g.44184820A>T
CM000669.1:g.44184820A>T
NC_000007.12:g.44151345A>T
NG_008847.1:g.49203T>A
NG_008847.2:g.57950T>A
ENST00000395796.8:c.*1311T>A
ENST00000616242.5:c.*433T>A
ENST00000683378.1:n.539T>A
ENST00000336642.9:c.347T>A
ENST00000345378.7:c.1316T>A
ENST00000403799.8:c.1313T>A
ENST00000671824.1:c.1376T>A
ENST00000672743.1:n.325T>A
ENST00000673284.1:c.1313T>A
ENST00000336642.8:n.365T>A
ENST00000345378.6:c.1316T>A
ENST00000395796.7:c.1310T>A
ENST00000403799.7:c.1313T>A
ENST00000437084.1:c.1262T>A
ENST00000459642.1:n.693T>A
ENST00000616242.4:n.1310T>A
NM_000162.3:c.1313T>A
NM_033507.1:c.1316T>A
NM_033508.1:c.1310T>A
NM_000162.4:c.1313T>A
NM_001354800.1:c.1313T>A
NM_001354801.1:c.302T>A
NM_001354802.1:c.173T>A
NM_001354803.1:c.347T>A
NM_033507.2:c.1316T>A
NM_033508.2:c.1310T>A
NM_000162.5:c.1313T>A
NM_033507.3:c.1316T>A
NM_033508.3:c.1310T>A

Uncertain Significance

• Met criteria codes: PP3 PP2 PM2_Supporting

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1313T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 438 (p.(Phe438Tyr)) 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 0.948, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual 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 19564454). Overall, this evidence supports the classification of c.1313T>A as a variant of uncertain significance for monogenic diabetes. CMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/20/2023): PP2, PP3, PM2_Supporting.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP 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).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant was identified in one individual 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 19564454).