Variant: NM_001306179.2:c.-187C>A

CA2480594443

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 53b95f49-e21c-488d-8873-bbdccc762e8c

Approved on: 2021-08-18

Published on: 2021-10-29

HGVS expressions

NM_001306179.2:c.-187C>A
NC_000012.12:g.120978582C>A
CM000674.2:g.120978582C>A
NC_000012.11:g.121416385C>A
CM000674.1:g.121416385C>A
NC_000012.10:g.119900768C>A
NG_011731.2:g.4837C>A
ENST00000257555.11:c.-187C>A
ENST00000257555.10:c.-187C>A
ENST00000400024.6:c.-187C>A
NM_000545.6:c.-187C>A
NM_001306179.1:c.-187C>A
NM_000545.8:c.-187C>A

Uncertain Significance

• Met criteria codes: PM1_Supporting PP4 PM2_Supporting

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.-187C>A variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent in gnomAD v2.1.1, and was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This individual had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.-187C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP4, PM1_Supporting, PM2_Supporting).

Met criteria codes

• PM1_Supporting: This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PP4: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1.

Not Met criteria codes

• PS4: This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).