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]

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Variant: NM_000545.8(HNF1A):c.367C>G (p.Leu123Val)

CA386959145

994547 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8f1e0f82-e40f-44ce-862e-7a1a64a82373

HGVS expressions

NM_000545.8:c.367C>G

NM_000545.8(HNF1A):c.367C>G (p.Leu123Val)

NC_000012.12:g.120988873C>G

CM000674.2:g.120988873C>G

NC_000012.11:g.121426676C>G

CM000674.1:g.121426676C>G

NC_000012.10:g.119911059C>G

NG_011731.2:g.15128C>G

ENST00000257555.11:c.367C>G

ENST00000257555.10:c.367C>G

ENST00000400024.6:c.367C>G

ENST00000402929.5:n.502C>G

ENST00000535955.5:n.43-8618C>G

ENST00000538626.2:n.191-8618C>G

ENST00000538646.5:c.367C>G

ENST00000540108.1:c.327-4647C>G

ENST00000541395.5:c.367C>G

ENST00000541924.5:c.367C>G

ENST00000543427.5:c.367C>G

ENST00000544413.2:c.367C>G

ENST00000544574.5:c.73-7744C>G

ENST00000560968.5:n.510C>G

ENST00000615446.4:c.-257-7389C>G

ENST00000617366.4:c.367C>G

NM_000545.5:c.367C>G

NM_000545.6:c.367C>G

NM_001306179.1:c.367C>G

NM_001306179.2:c.367C>G

Likely Pathogenic

PM1_Supporting PP3 PM2_Supporting PP4_Moderate PP1_Strong

PS4 PM5

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.367C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 123 (p.(Leu123Val)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.777, which is greater than the MDEP threshold of 0.70 (PP3) and is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate (ClinVar ID 994547, internal lab contributor). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes in at least 5 meioses in 1 family (internal lab contributors). Two other missense variants, c.368T>C (p.Leu123Pro) and c.368T>G (p.Leu123Arg), have been classified as VUS by the ClinGen MDEP; therefore PM5 will not be applied. In summary, c.367C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting.

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.777, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors).

PP1_Strong

This variant segregated with diabetes in at least 5 meioses in 1 family (internal lab contributors)

PS4

This variant was identified in two unrelated individuals with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate (ClinVar ID 994547, internal lab contributor)

PM5

Two other missense variants, c.368T>C (p.Leu123Pro) and c.368T>G (p.Leu123Arg) have been classified as a VUS by the ClinGen MDEP VCEP; therefore PM5 will not be applied.

Approved on: 2023-08-23

Published on: 2023-08-23

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