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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.2:c.653A>G

CA386964799

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c1cda891-2e75-4407-acc2-74048ff44214

HGVS expressions

NM_001306179.2:c.653A>G

NC_000012.12:g.120993646A>G

CM000674.2:g.120993646A>G

NC_000012.11:g.121431449A>G

CM000674.1:g.121431449A>G

NC_000012.10:g.119915832A>G

NG_011731.2:g.19901A>G

ENST00000257555.11:c.653A>G

ENST00000257555.10:c.653A>G

ENST00000400024.6:c.653A>G

ENST00000402929.5:n.788A>G

ENST00000535955.5:n.43-3845A>G

ENST00000538626.2:n.191-3845A>G

ENST00000538646.5:c.527-518A>G

ENST00000540108.1:c.*93A>G

ENST00000541395.5:c.653A>G

ENST00000541924.5:c.653A>G

ENST00000543427.5:c.633+20A>G

ENST00000544413.2:c.653A>G

ENST00000544574.5:c.73-2971A>G

ENST00000560968.5:c.796A>G

ENST00000615446.4:c.-257-2616A>G

ENST00000617366.4:c.586+67A>G

NM_000545.5:c.653A>G

NM_000545.6:c.653A>G

NM_001306179.1:c.653A>G

NM_000545.8:c.653A>G

Pathogenic

PM1_Supporting PM2_Supporting PS4 PP3 PP1_Strong PP4_Moderate

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.653A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 218 (p.Tyr218Cys)) of NM_000545.8. 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 10872540, PMID: 17286239, internal lab contributors). At least one individual had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; PMID: 17286239, internal lab contributors). In summary, c.653A>G meets the criteria to be classified as 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, PS4, 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).

PM2_Supporting

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

PS4

This variant was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 10872540, PMID: 17286239, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP1_Strong

This variant segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; PMID: 17286239, internal lab contributors).

PP4_Moderate

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

Approved on: 2024-01-22

Published on: 2024-01-22

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