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.1135C>G (p.Pro379Ala)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA6831955

431970 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2e13c2de-6b67-4738-b89f-f88858c71a3b

Approved on: 2025-09-02

Published on: 2025-09-02

HGVS expressions

NM_000545.8:c.1135C>G

NM_000545.8(HNF1A):c.1135C>G (p.Pro379Ala)

NC_000012.12:g.120996568C>G

CM000674.2:g.120996568C>G

NC_000012.11:g.121434371C>G

CM000674.1:g.121434371C>G

NC_000012.10:g.119918754C>G

NG_011731.2:g.22823C>G

ENST00000560968.6:c.809C>G

ENST00000257555.11:c.1135C>G

ENST00000257555.10:c.1135C>G

ENST00000400024.6:c.1135C>G

ENST00000402929.5:n.1270C>G

ENST00000535955.5:n.43-923C>G

ENST00000538626.2:n.191-923C>G

ENST00000538646.5:c.*111C>G

ENST00000540108.1:c.*575C>G

ENST00000541395.5:c.1135C>G

ENST00000541924.5:c.*149C>G

ENST00000543255.1:n.179C>G

ENST00000543427.5:c.634-36C>G

ENST00000544413.2:c.1135C>G

ENST00000544574.5:c.73-49C>G

ENST00000560968.5:c.952C>G

ENST00000615446.4:c.-78C>G

ENST00000617366.4:c.587-1066C>G

NM_000545.5:c.1135C>G

NM_000545.6:c.1135C>G

NM_001306179.1:c.1135C>G

NM_001306179.2:c.1135C>G

Benign

PM5_Supporting PP3 BA1

BP5 PS4 PM2 PM1

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.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, 23348805, 29207974, 21761282, 23607861), the Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.0005027, which is greater than the MDEP threshold for BA1 (>0.0001) (BA1). Therefore, PS4 cannot be applied. Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but this variant has a greater Grantham distance than p.Pro379Ala (PM5_Supporting). In summary, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BA1, PP3, PM5_Supporting. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at https://t2d.hugeamp.org/).

PM5_Supporting

Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Ala (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

BA1

This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00050268, which is greater than the MDEP threshold for BA1 (>0.0001) (BA1).

BP5

Identified in a case with HNF4A R114W, which has not been classified as a causal monogenic diabetes variant.

PS4

This variant was identified in >20 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar ID 431970, PMID:18003757, PMID: 23348805, PMID: 29207974, PMID: 21761282, PMID: 23607861, internal laboratory collaborators).

PM2

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

PM1

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

Curation History

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