Variant: NM_000162.5(GCK):c.1386G>T (p.Met462Ile)

CA213763

36202 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 0e18154f-01a4-4c6d-aa94-8917e1b837fd

Approved on: 2023-09-01

Published on: 2023-09-01

HGVS expressions

NM_000162.5:c.1386G>T
NM_000162.5(GCK):c.1386G>T (p.Met462Ile)
NC_000007.14:g.44145148C>A
CM000669.2:g.44145148C>A
NC_000007.13:g.44184747C>A
CM000669.1:g.44184747C>A
NC_000007.12:g.44151272C>A
NG_008847.1:g.49276G>T
NG_008847.2:g.58023G>T
ENST00000395796.8:c.*1384G>T
ENST00000616242.5:c.*506G>T
ENST00000683378.1:n.612G>T
ENST00000336642.9:c.420G>T
ENST00000345378.7:c.1389G>T
ENST00000403799.8:c.1386G>T
ENST00000671824.1:c.1449G>T
ENST00000672743.1:n.381+17G>T
ENST00000673284.1:c.1369+17G>T
ENST00000336642.8:n.438G>T
ENST00000345378.6:c.1389G>T
ENST00000395796.7:c.1383G>T
ENST00000403799.7:c.1386G>T
ENST00000437084.1:c.1335G>T
ENST00000459642.1:n.766G>T
ENST00000616242.4:n.1383G>T
NM_000162.3:c.1386G>T
NM_033507.1:c.1389G>T
NM_033508.1:c.1383G>T
NM_000162.4:c.1386G>T
NM_001354800.1:c.1369+17G>T
NM_001354801.1:c.375G>T
NM_001354802.1:c.229+17G>T
NM_001354803.1:c.420G>T
NM_033507.2:c.1389G>T
NM_033508.2:c.1383G>T
NM_033507.3:c.1389G>T
NM_033508.3:c.1383G>T
NM_001354803.2:c.420G>T

Likely Benign

• Met criteria codes: PP2 BS2 BP5

• Not Met criteria codes: PS4 PP4 PP3 PM2 BS1 BP4

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1386G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 462 (p.(Met462Ile)) 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 REVEL score of 0.45, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant was identified in at least 5 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 (internal lab contributors). This variant was identified in at least two individuals with a normal fasting glucose (BS2) (PMID: 24097065). The Popmax filtering allele frequency of the c.1386G>T variant in gnomAD v2.1.1 is 0.00001159, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1386G>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, BP5, BS2.

Met criteria codes

• 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).
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: This variant was identified in a patient with an alternate molecular basis for disease (BP5; D, internal lab contributors).

Not Met criteria codes

• PS4: This variant was identified in at least 5 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 (internal lab contributors).
• PP4: This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors).
• PP3: This variant has a REVEL score of 0.45, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.
• PM2: The PopMax filtering allele frequency of the c.1386G>T variant in gnomAD v2.1.1 is 0.00001159, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied.
• BS1: The PopMax filtering allele frequency of the c.1386G>T variant in gnomAD v2.1.1 is 0.00001159, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
• BP4: This variant has a REVEL score of 0.45, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.