Variant: NM_001306179.2:c.28A>C

CA386952326

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: d2720f4a-e81f-4895-b17c-ff35a92cff70

HGVS expressions

NM_001306179.2:c.28A>C
NC_000012.12:g.120978796A>C
CM000674.2:g.120978796A>C
NC_000012.11:g.121416599A>C
CM000674.1:g.121416599A>C
NC_000012.10:g.119900982A>C
NG_011731.2:g.5051A>C
ENST00000257555.11:c.28A>C
ENST00000257555.10:c.28A>C
ENST00000400024.6:c.28A>C
ENST00000402929.5:n.163A>C
ENST00000535955.5:n.42+104A>C
ENST00000538626.2:n.146A>C
ENST00000538646.5:c.28A>C
ENST00000540108.1:c.28A>C
ENST00000541395.5:c.28A>C
ENST00000541924.5:c.28A>C
ENST00000543427.5:c.28A>C
ENST00000544413.2:c.28A>C
ENST00000544574.5:c.28A>C
ENST00000560968.5:n.171A>C
ENST00000615446.4:c.-258+85A>C
ENST00000617366.4:c.28A>C
NM_000545.5:c.28A>C
NM_000545.6:c.28A>C
NM_001306179.1:c.28A>C
NM_000545.8:c.28A>C

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM1_Supporting PS2 PM2_Supporting

• Not Met criteria codes: PS4 PP3

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.28A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to proline at codon 10 (p.(Thr10Pro)) of NM_000545.8. This variant is located within the DNA binding of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate; internal lab contributor). Lastly, this variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A (PS2; PMID:28701371). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PM2_Suporting, PP4_Moderate, PS2.

Met criteria codes

• PP4_Moderate: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate).
• PM1_Supporting: This variant is located within the DNA binding of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PS2: This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A (PS2; [PMID:28701371]).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-03-25

Published on: 2022-07-12