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]

Variant: NM_000545.8(HNF1A):c.73G>C (p.Ala25Pro)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA386952675

1675059 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5f10758c-bad1-4287-a1b8-5260fd3ed7f8

Approved on: 2025-06-18

Published on: 2025-06-18

HGVS expressions

NM_000545.8:c.73G>C

NM_000545.8(HNF1A):c.73G>C (p.Ala25Pro)

NC_000012.12:g.120978841G>C

CM000674.2:g.120978841G>C

NC_000012.11:g.121416644G>C

CM000674.1:g.121416644G>C

NC_000012.10:g.119901027G>C

NG_011731.2:g.5096G>C

ENST00000560968.6:c.73G>C

ENST00000257555.11:c.73G>C

ENST00000257555.10:c.73G>C

ENST00000400024.6:c.73G>C

ENST00000402929.5:n.208G>C

ENST00000535955.5:n.42+149G>C

ENST00000538626.2:n.190+1G>C

ENST00000538646.5:c.73G>C

ENST00000540108.1:c.73G>C

ENST00000541395.5:c.73G>C

ENST00000541924.5:c.73G>C

ENST00000543427.5:c.73G>C

ENST00000544413.2:c.73G>C

ENST00000544574.5:c.72+1G>C

ENST00000560968.5:c.216G>C

ENST00000615446.4:c.-258+130G>C

ENST00000617366.4:c.73G>C

NM_000545.5:c.73G>C

NM_000545.6:c.73G>C

NM_001306179.1:c.73G>C

NM_001306179.2:c.73G>C

Uncertain Significance

PM1_Supporting PM2_Supporting

PS4 PP3 PP4 BP4

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 HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.684, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested, so PP4 cannot be applied (PMID: 15841481). 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 (PMIDs: 15841481, 21224407). In summary, c.73G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting.

PM1_Supporting

This variant is in the dimerization domain.

PM2_Supporting

This variant is absent from gnomAD.

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 (PMIDs: 15841481, 21224407).

PP3

This variant has a REVEL score of 0.684, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function.

PP4

This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested, so PP4 cannot be applied (PMID: 15841481).

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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