Variant: NM_001306179.2:c.140G>A

CA386953149

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: f000737d-a959-4e25-9681-b7cff532d53d

Approved on: 2022-04-02

Published on: 2022-07-12

HGVS expressions

NM_001306179.2:c.140G>A
NC_000012.12:g.120978908G>A
CM000674.2:g.120978908G>A
NC_000012.11:g.121416711G>A
CM000674.1:g.121416711G>A
NC_000012.10:g.119901094G>A
NG_011731.2:g.5163G>A
ENST00000257555.11:c.140G>A
ENST00000257555.10:c.140G>A
ENST00000400024.6:c.140G>A
ENST00000402929.5:n.275G>A
ENST00000535955.5:n.42+216G>A
ENST00000538626.2:n.190+68G>A
ENST00000538646.5:c.140G>A
ENST00000540108.1:c.140G>A
ENST00000541395.5:c.140G>A
ENST00000541924.5:c.140G>A
ENST00000543427.5:c.140G>A
ENST00000544413.2:c.140G>A
ENST00000544574.5:c.72+68G>A
ENST00000560968.5:n.283G>A
ENST00000615446.4:c.-258+197G>A
ENST00000617366.4:c.140G>A
NM_000545.5:c.140G>A
NM_000545.6:c.140G>A
NM_001306179.1:c.140G>A
NM_000545.8:c.140G>A

Uncertain Significance

• Met criteria codes: BS3_Supporting PM2_Supporting

• Not Met criteria codes: PP4 PM5

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.140G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to glutamate at codon 47 (p.(Gly47Glu)) of NM_000545.8. Functional studies demonstrated the p.Gly47Arg protein has normal nuclear localization and transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 12574234) (BS3_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.139G>C (p.(Gly47Arg)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PP4 cannot be applied (PMID: 12574234, internal lab contributor). In summary, c.140G>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 (specification version 1.0, approved 9/30/21): BS3_Supporting, PM2_supporting

Met criteria codes

• BS3_Supporting: Normal nuclear localization and transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 12574234).
• PM2_Supporting: Absent from gnomAD.

Not Met criteria codes

• PP4: This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 12574234, internal lab contributor).
• PM5: Another missense variant, c.139G>C (p.(Gly47Arg)), has been classified as a VUS by the ClinGen MDEP.