Variant: NM_001306179.2:c.34C>T

CA386952410

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: fbb17e31-b6fb-4699-b296-0a04c9c7eb28

HGVS expressions

NM_001306179.2:c.34C>T
NC_000012.12:g.120978802C>T
CM000674.2:g.120978802C>T
NC_000012.11:g.121416605C>T
CM000674.1:g.121416605C>T
NC_000012.10:g.119900988C>T
NG_011731.2:g.5057C>T
ENST00000257555.11:c.34C>T
ENST00000257555.10:c.34C>T
ENST00000400024.6:c.34C>T
ENST00000402929.5:n.169C>T
ENST00000535955.5:n.42+110C>T
ENST00000538626.2:n.152C>T
ENST00000538646.5:c.34C>T
ENST00000540108.1:c.34C>T
ENST00000541395.5:c.34C>T
ENST00000541924.5:c.34C>T
ENST00000543427.5:c.34C>T
ENST00000544413.2:c.34C>T
ENST00000544574.5:c.34C>T
ENST00000560968.5:n.177C>T
ENST00000615446.4:c.-258+91C>T
ENST00000617366.4:c.34C>T
NM_000545.5:c.34C>T
NM_000545.6:c.34C>T
NM_001306179.1:c.34C>T
NM_000545.8:c.34C>T

Likely Pathogenic

• Met criteria codes: PM1_Supporting PP3 PP4 PP1_Moderate PM2_Supporting PS4_Moderate

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.34C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 12 (p.(Leu12Phe)) of NM_000545.8. This variant failed quality control metrics in gnomAD v2.1.1, but is absent in gnomAD v3.1.2 (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 0.925, which is greater than the MDEP threshold of 0.70 (PP3). Further, this variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors).  This variant segregated with diabetes, with three informative meioses in two families with MODY (PP1_Moderate; internal lab contributors). Lastly, this variant was identified in four unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; internal lab contributors, PMID:15928245). 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, PP1_Moderate, PS4_Moderate.

Met criteria codes

• 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).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP threshold of 0.70 (PP3)
• PP4: this variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors).
• PP1_Moderate: This variant segregated with diabetes, with three informative meioses in two families with MODY (PP1_Moderate; internal lab contributors).
• PM2_Supporting: This variant failed quality control checks in gnomAD v2.1.1, and is absent in gnomAD v3.1.1 (PM2_Supporting).
• PS4_Moderate: This variant was identified in four unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; internal lab contributors, PMID:15928245).

Approved on: 2022-03-25

Published on: 2022-07-12