Variant: NM_001306179.2:c.58G>A

CA386952577

1033090 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 890f4355-b322-4d63-ab2e-02ceb1436a6a

HGVS expressions

NM_001306179.2:c.58G>A
NC_000012.12:g.120978826G>A
CM000674.2:g.120978826G>A
NC_000012.11:g.121416629G>A
CM000674.1:g.121416629G>A
NC_000012.10:g.119901012G>A
NG_011731.2:g.5081G>A
ENST00000257555.11:c.58G>A
ENST00000257555.10:c.58G>A
ENST00000400024.6:c.58G>A
ENST00000402929.5:n.193G>A
ENST00000535955.5:n.42+134G>A
ENST00000538626.2:n.176G>A
ENST00000538646.5:c.58G>A
ENST00000540108.1:c.58G>A
ENST00000541395.5:c.58G>A
ENST00000541924.5:c.58G>A
ENST00000543427.5:c.58G>A
ENST00000544413.2:c.58G>A
ENST00000544574.5:c.58G>A
ENST00000560968.5:n.201G>A
ENST00000615446.4:c.-258+115G>A
ENST00000617366.4:c.58G>A
NM_000545.5:c.58G>A
NM_000545.6:c.58G>A
NM_001306179.1:c.58G>A
NM_000545.8:c.58G>A
NM_000545.8(HNF1A):c.58G>A (p.Gly20Arg)

Pathogenic

• Met criteria codes: PS3_Supporting PM2_Supporting PP4_Moderate PP1_Strong PS4_Moderate PM1_Supporting PP3

• Not Met criteria codes: PS1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.58G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 20 (p.(G20R)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) 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 0.956, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies demonstrated the p.Gly20Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:12107757). This variant is absent in the gnomAD v2.1.1 European non-Finnish population and has one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). 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, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor), with at least one of these individuals having a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with at least 5 informative meioses in two families with MODY (PP1_Strong; PMID:15657605, internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PP4_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting).

Met criteria codes

• PS3_Supporting: Functional studies demonstrated the p.Gly20Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID:12107757).
• PM2_Supporting: This variant is absent in the gnomAD v2.1.1 European non-Finnish population and has one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting).
• PP4_Moderate: 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, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor).
• PP1_Strong: This variant segregated with diabetes, with at least 5 informative meioses in two families with MODY (PP1_Strong; PMID:15657605, internal lab contributors).
• PS4_Moderate: This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:10588527, PMID:15657605, ClinVar ID:1033090, internal lab contributors).
• PM1_Supporting: This variant is located within the dimerization domain (codons 1-32) 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 0.956, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS1: The nucleotide change c.58G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.58G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP.

Approved on: 2021-08-18

Published on: 2021-10-29