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_001306179.2:c.225C>A

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA386953852

1676700 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3eb53682-f56b-42df-a731-683afb29a138

Approved on: 2025-11-26

Published on: 2025-11-26

HGVS expressions

NM_001306179.2:c.225C>A

NC_000012.12:g.120978993C>A

CM000674.2:g.120978993C>A

NC_000012.11:g.121416796C>A

CM000674.1:g.121416796C>A

NC_000012.10:g.119901179C>A

NG_011731.2:g.5248C>A

ENST00000560968.6:c.225C>A

ENST00000257555.11:c.225C>A

ENST00000257555.10:c.225C>A

ENST00000400024.6:c.225C>A

ENST00000402929.5:n.360C>A

ENST00000535955.5:n.42+301C>A

ENST00000538626.2:n.190+153C>A

ENST00000538646.5:c.225C>A

ENST00000540108.1:c.225C>A

ENST00000541395.5:c.225C>A

ENST00000541924.5:c.225C>A

ENST00000543427.5:c.225C>A

ENST00000544413.2:c.225C>A

ENST00000544574.5:c.72+153C>A

ENST00000560968.5:c.368C>A

ENST00000615446.4:c.-258+282C>A

ENST00000617366.4:c.225C>A

NM_000545.5:c.225C>A

NM_000545.6:c.225C>A

NM_001306179.1:c.225C>A

NM_000545.8:c.225C>A

Uncertain Significance

PM2_Supporting

BP4 PS1 PP3 PP4

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.225C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 0.000001240, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant has a REVEL score of 0.564, 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 calculated MODY probability is <50%; therefore, PP4 could not be applied (internal lab contributors). The nucleotide change c.225C>G, which causes the same amino acid change, has been classified as a VUS by the ClinGen MDEP; therefore, PS1 does not apply. In summary, c.225C>A 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 3.1.0, approved 10/10/2025): PM2_Supporting.

PM2_Supporting

This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 0.000001240, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting).

BP4

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

PS1

The nucleotide change c.225C>G, which causes the same amino acid change, has been classified as a VUS by the ClinGen MDEP; therefore, PS1 does not apply.

PP3

This variant has a REVEL score of 0.564, 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(s) with diabetes; however, the calculated MODY probability is <50% (internal lab contributors).

Curation History

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