Variant: NM_001306179.2:c.397G>A

CA386959501

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 2df517d3-5781-4545-aaca-c9b51f71e0a1

HGVS expressions

NM_001306179.2:c.397G>A
NC_000012.12:g.120988903G>A
CM000674.2:g.120988903G>A
NC_000012.11:g.121426706G>A
CM000674.1:g.121426706G>A
NC_000012.10:g.119911089G>A
NG_011731.2:g.15158G>A
ENST00000257555.11:c.397G>A
ENST00000257555.10:c.397G>A
ENST00000400024.6:c.397G>A
ENST00000402929.5:n.532G>A
ENST00000535955.5:n.43-8588G>A
ENST00000538626.2:n.191-8588G>A
ENST00000538646.5:c.397G>A
ENST00000540108.1:c.327-4617G>A
ENST00000541395.5:c.397G>A
ENST00000541924.5:c.397G>A
ENST00000543427.5:c.397G>A
ENST00000544413.2:c.397G>A
ENST00000544574.5:c.73-7714G>A
ENST00000560968.5:n.540G>A
ENST00000615446.4:c.-257-7359G>A
ENST00000617366.4:c.397G>A
NM_000545.5:c.397G>A
NM_000545.6:c.397G>A
NM_001306179.1:c.397G>A
NM_000545.8:c.397G>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS4_Moderate PM1_Supporting PP1 PP3

• Not Met criteria codes: PS3 PP4

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.397G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 133 (p.(Val133Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.974, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 10754480, PMID 21170474, PMID 17573900, internal lab contributors). Due to lack of individual level data and/or lack of testing for HNF4A, PP4 could not be applied to any of these cases. This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID 10754480). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 21170474). In summary, the c.397G>A 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): PS4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PS4_Moderate: This variant was identified in at least five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 10754480, PMID 21170474, PMID 17573900, internal lab contributors).
• PM1_Supporting: This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PP1: This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID 10754480).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.974, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS3: Galan 2011 (PMID: 21170474) used Mouse cDNA- Taken from Paris file “Functional analysis on mouse cDNA. Transactivation of the HNF4A P2 promoter seemed unaltered in Cos7 and MIN6 cell lines. Defective for other promoters (GLUT2, Luciferase and RIP). EMSA : Binding impaired to one of the 2 probes that were tested.” ​
• PP4: Could not apply calculator to members of family used for PP1 (PMID: 10754480) because no individual level data is known. Other cases used for PS4 were not tested for HNF4A.

Approved on: 2022-06-24

Published on: 2022-06-24