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.1768G>A (p.Val590Met)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386973441

447484 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3fa64ca7-d2ab-4397-85da-22418f47c681

Approved on: 2025-10-03

Published on: 2025-10-03

HGVS expressions

NM_000545.8:c.1768G>A

NM_000545.8(HNF1A):c.1768G>A (p.Val590Met)

NC_000012.12:g.120999627G>A

CM000674.2:g.120999627G>A

NC_000012.11:g.121437430G>A

CM000674.1:g.121437430G>A

NC_000012.10:g.119921813G>A

NG_011731.2:g.25882G>A

ENST00000560968.6:c.*515G>A

ENST00000257555.11:c.1768G>A

ENST00000257555.10:c.1768G>A

ENST00000540108.1:c.*1208G>A

ENST00000541395.5:c.1861G>A

ENST00000543427.5:c.1231G>A

ENST00000544413.2:c.1789G>A

ENST00000560968.5:c.1585G>A

ENST00000615446.4:c.556G>A

ENST00000617366.4:c.*177G>A

NM_000545.5:c.1768G>A

NM_000545.6:c.1768G>A

NM_001306179.1:c.1789G>A

NM_001306179.2:c.1789G>A

Uncertain Significance

PP3 PP4 PM2 BS1 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 3.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590 (p.(Val590Met)) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.00000553 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.442, 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 diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, therefore PP4 does not apply (PMID: 33477506). In summary, c.1768C>G 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 3.0.0, approved 6/30/2025): none.

PP3

This variant has a REVEL score of 0.442, 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 diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 33477506).

PM2

This variant has a Grpmax filtering allele frequency of 0.00000553 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

BS1

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

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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