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.1265T>C (p.Leu422Pro)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA214258

36797 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8a58786f-33c1-44e0-92bf-e62ebc37f22d

Approved on: 2025-07-24

Published on: 2025-07-24

HGVS expressions

NM_000545.8:c.1265T>C

NM_000545.8(HNF1A):c.1265T>C (p.Leu422Pro)

NC_000012.12:g.120996698T>C

CM000674.2:g.120996698T>C

NC_000012.11:g.121434501T>C

CM000674.1:g.121434501T>C

NC_000012.10:g.119918884T>C

NG_011731.2:g.22953T>C

ENST00000560968.6:c.*12T>C

ENST00000257555.11:c.1265T>C

ENST00000257555.10:c.1265T>C

ENST00000400024.6:c.1265T>C

ENST00000402929.5:n.1400T>C

ENST00000535955.5:n.43-793T>C

ENST00000538626.2:n.191-793T>C

ENST00000538646.5:c.*241T>C

ENST00000540108.1:c.*705T>C

ENST00000541395.5:c.1265T>C

ENST00000541924.5:c.*279T>C

ENST00000543255.1:n.309T>C

ENST00000543427.5:c.728T>C

ENST00000544413.2:c.1265T>C

ENST00000544574.5:c.*28T>C

ENST00000560968.5:c.1082T>C

ENST00000615446.4:c.53T>C

ENST00000617366.4:c.587-936T>C

NM_000545.5:c.1265T>C

NM_000545.6:c.1265T>C

NM_001306179.1:c.1265T>C

NM_001306179.2:c.1265T>C

Uncertain Significance

BS1 PM2 PP4 PP3

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.1265T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 422 (p.(Leu422Pro)) of NM_000545.8. The Grpmax filtering allele frequency of the c.1265T>C variant in gnomAD v4.1.0 is 0.0000036, 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 0.604, 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 (PMID: 30293189). In summary, c.1265T>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 3.0.0, approved 6/30/2025): none.

BS1

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

PM2

The Grpmax filtering allele frequency of the c.1265T>C variant in gnomAD v4.1.0 is 0.0000036, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

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:30293189).

PP3

This variant has a REVEL score of 0.604, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function.

Curation History

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