Variant: NM_001306179.2:c.35T>G

CA386952415

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: a3980a94-b2d6-4fb1-8eab-b8d75f88188f

HGVS expressions

NM_001306179.2:c.35T>G
NC_000012.12:g.120978803T>G
CM000674.2:g.120978803T>G
NC_000012.11:g.121416606T>G
CM000674.1:g.121416606T>G
NC_000012.10:g.119900989T>G
NG_011731.2:g.5058T>G
ENST00000257555.11:c.35T>G
ENST00000257555.10:c.35T>G
ENST00000400024.6:c.35T>G
ENST00000402929.5:n.170T>G
ENST00000535955.5:n.42+111T>G
ENST00000538626.2:n.153T>G
ENST00000538646.5:c.35T>G
ENST00000540108.1:c.35T>G
ENST00000541395.5:c.35T>G
ENST00000541924.5:c.35T>G
ENST00000543427.5:c.35T>G
ENST00000544413.2:c.35T>G
ENST00000544574.5:c.35T>G
ENST00000560968.5:n.178T>G
ENST00000615446.4:c.-258+92T>G
ENST00000617366.4:c.35T>G
NM_000545.5:c.35T>G
NM_000545.6:c.35T>G
NM_001306179.1:c.35T>G
NM_000545.8:c.35T>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PM1_Supporting PM5_Supporting PP3

• Not Met criteria codes: PS4 PP1

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.35T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 12 (p.(Leu12Arg)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within the dimerization domain 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 0.9409, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to sulfonylurea) (PP4_Moderate; internal lab contributors). Lastly, another missense variant, c.34C>G, (p.Leu12Val), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate, PM5_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP4_Moderate: This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to sulfonylurea) (PP4_Moderate; [internal lab contributors]).
• PM1_Supporting: This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PM5_Supporting: Another missense variant, [c.34C>G, p.Leu12Val], has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9409, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-03-30

Published on: 2022-07-12