Variant: NM_000545.8(HNF1A):c.1745A>G (p.His582Arg)

CA214288

36811 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 860b8766-c061-4fc3-a76f-1c999833705b

Approved on: 2024-08-01

Published on: 2024-08-01

HGVS expressions

NM_000545.8:c.1745A>G
NM_000545.8(HNF1A):c.1745A>G (p.His582Arg)
NC_000012.12:g.120999604A>G
CM000674.2:g.120999604A>G
NC_000012.11:g.121437407A>G
CM000674.1:g.121437407A>G
NC_000012.10:g.119921790A>G
NG_011731.2:g.25859A>G
ENST00000560968.6:c.*492A>G
ENST00000257555.11:c.1745A>G
ENST00000257555.10:c.1745A>G
ENST00000540108.1:c.*1185A>G
ENST00000541395.5:c.1838A>G
ENST00000543427.5:c.1208A>G
ENST00000544413.2:c.1766A>G
ENST00000560968.5:c.1562A>G
ENST00000615446.4:c.533A>G
ENST00000617366.4:c.*154A>G
NM_000545.5:c.1745A>G
NM_000545.6:c.1745A>G
NM_001306179.1:c.1766A>G
NM_001306179.2:c.1766A>G

Likely Benign

• Met criteria codes: PP4 BS3_Supporting BS1

• Not Met criteria codes: PS4 PP3 PM2

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 2.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1745A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 582 (p.(His582Arg)) of NM_000545.8. This variant has a REVEL score of 0.6869, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function, and functional studies demonstrated the p.His582Arg protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003916, which is greater than or equal to the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in at least 3 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar ID 36811, PMID: 27913849, PMID: 23624530, PMID: 23348805, internal lab contributor). One individual has a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with a non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4). In summary, the c.1745A>G variant meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 8/4/2022): PP4, BS1, BS3_Supporting.

Met criteria codes

• PP4: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with a non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4).
• BS3_Supporting: Functional studies demonstrated the p.His582Arg protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting).
• BS1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003916, which is greater than or equal to the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1).

Not Met criteria codes

• PS4: This variant was identified in at least 3 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar ID 36811, PMID: 27913849, PMID: 23624530, PMID: 23348805, internal lab contributor).
• PP3: This variant has a REVEL score of 0.6869, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline