Variant: NM_001306179.2:c.59G>A

CA386952580

1327598 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 017c9f8b-daac-4057-a465-ca40602c4be1

Approved on: 2025-07-24

Published on: 2025-07-24

HGVS expressions

NM_001306179.2:c.59G>A
NC_000012.12:g.120978827G>A
CM000674.2:g.120978827G>A
NC_000012.11:g.121416630G>A
CM000674.1:g.121416630G>A
NC_000012.10:g.119901013G>A
NG_011731.2:g.5082G>A
ENST00000560968.6:c.59G>A
ENST00000257555.11:c.59G>A
ENST00000257555.10:c.59G>A
ENST00000400024.6:c.59G>A
ENST00000402929.5:n.194G>A
ENST00000535955.5:n.42+135G>A
ENST00000538626.2:n.177G>A
ENST00000538646.5:c.59G>A
ENST00000540108.1:c.59G>A
ENST00000541395.5:c.59G>A
ENST00000541924.5:c.59G>A
ENST00000543427.5:c.59G>A
ENST00000544413.2:c.59G>A
ENST00000544574.5:c.59G>A
ENST00000560968.5:c.202G>A
ENST00000615446.4:c.-258+116G>A
ENST00000617366.4:c.59G>A
NM_000545.5:c.59G>A
NM_000545.6:c.59G>A
NM_001306179.1:c.59G>A
NM_000545.8:c.59G>A

Likely Pathogenic

• Met criteria codes: PM1_Supporting PM2_Supporting PM5_Supporting PP3 PP1_Strong

• Not Met criteria codes: PP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.59G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to glutamic acid at codon 20 (p.(G20E)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Glu (PM5_Supporting). This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant was identified in a family with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, and segregated with diabetes with eight informative meioses in one family with MODY (PP1_Strong; PMID: 27323672). At least one individual in this family had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 27323672). Taken together, this evidence supports the classification of c.59G>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP1_strong, PP3, PM1_supporting, PM2_supporting, PM5_supporting.

Met criteria codes

• PM1_Supporting: This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.1.0, absent
• PM5_Supporting: Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Glu (PM5_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP threshold of 0.70 (PP3).
• PP1_Strong: This variant segregated with diabetes, with eight informative meioses in one family with MODY (PP1_Strong; PMID: 27323672).

Not Met criteria codes

• PP4: This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 27323672).