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.649G>A (p.Asp217Asn)

CA4239564

911631 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 074db8ad-1490-4c1f-a15b-103a2b17ef3f

HGVS expressions

NM_000162.5:c.649G>A

NM_000162.5(GCK):c.649G>A (p.Asp217Asn)

NC_000007.14:g.44149790C>T

CM000669.2:g.44149790C>T

NC_000007.13:g.44189389C>T

CM000669.1:g.44189389C>T

NC_000007.12:g.44155914C>T

NG_008847.1:g.44634G>A

NG_008847.2:g.53381G>A

ENST00000395796.8:c.*647G>A

ENST00000616242.5:c.649G>A

ENST00000682635.1:n.1135G>A

ENST00000345378.7:c.652G>A

ENST00000403799.8:c.649G>A

ENST00000671824.1:c.649G>A

ENST00000673284.1:c.649G>A

ENST00000345378.6:c.652G>A

ENST00000395796.7:c.646G>A

ENST00000403799.7:c.649G>A

ENST00000437084.1:c.598G>A

ENST00000616242.4:n.646G>A

NM_000162.3:c.649G>A

NM_033507.1:c.652G>A

NM_033508.1:c.646G>A

NM_000162.4:c.649G>A

NM_001354800.1:c.649G>A

NM_033507.2:c.652G>A

NM_033508.2:c.646G>A

NM_033507.3:c.652G>A

NM_033508.3:c.646G>A

Benign

PP2 BS2 BS1 BP2

PS4 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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.649G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 217 (p.(Asp217Asn)) of [transcript, e.g. NM_000545.8]. 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 Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00005377, which is greater than the MDEP threshold for BS1 (≥0.0.00004) (BS1). This variant was identified in four 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). Additionally, this variant was identified in an individual with a normal fasting glucose (BS2) (internal lab contributor). This variant has been observed in cis with the variant GCK c.781G>A (p.Gly261Arg) (PMID:22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). Lastly, functional studies suggest that the p.Asp217Asn protein has increased activity (RAI=2.0); however, the thermostability and protein interactions were not analyzed and therefore neither PS3 or BS3 can be applied (PMID 22611063). In summary, c.649G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS1, BS2, BP2, PP2.

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

This variant was identified in an individual with a normal fasting glucose (BS2) (internal lab contributor).

BS1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00005377, which is greater than the MDEP threshold for BS1 (≥0.00004) (BS1).

BP2

This variant has been observed in cis with the variant GCK c.781G>A (p.Gly261Arg) (PMID:22611063), which is classified as pathogenic by the ClinGen MDEP (BP2).

PS4

This variant was identified in four 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).

PS3

Functional studies suggest that the p.Asp217Asn protein has increased activity (RAI=2.0), however the RSI and protein interactions were not analyzed and therefore neither PS3 or BS3 can be applied (PMID 22611063).

Approved on: 2023-08-13

Published on: 2023-08-13

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