Variant: NM_000545.8(HNF1A):c.434C>T (p.Ser145Phe)

CA386959990

447489 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: e182ccbb-ffe1-4d68-9dfa-81ce551eed87

HGVS expressions

NM_000545.8:c.434C>T
NM_000545.8(HNF1A):c.434C>T (p.Ser145Phe)
NC_000012.12:g.120988940C>T
CM000674.2:g.120988940C>T
NC_000012.11:g.121426743C>T
CM000674.1:g.121426743C>T
NC_000012.10:g.119911126C>T
NG_011731.2:g.15195C>T
ENST00000257555.11:c.434C>T
ENST00000257555.10:c.434C>T
ENST00000400024.6:c.434C>T
ENST00000402929.5:n.569C>T
ENST00000535955.5:n.43-8551C>T
ENST00000538626.2:n.191-8551C>T
ENST00000538646.5:c.434C>T
ENST00000540108.1:c.327-4580C>T
ENST00000541395.5:c.434C>T
ENST00000541924.5:c.434C>T
ENST00000543427.5:c.434C>T
ENST00000544413.2:c.434C>T
ENST00000544574.5:c.73-7677C>T
ENST00000560968.5:n.577C>T
ENST00000615446.4:c.-257-7322C>T
ENST00000617366.4:c.434C>T
NM_000545.5:c.434C>T
NM_000545.6:c.434C>T
NM_001306179.1:c.434C>T
NM_001306179.2:c.434C>T

Pathogenic

• Met criteria codes: PM2_Supporting PP1_Strong PS4_Moderate PP3 PM1

• 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.434C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 145 (p.(Ser145Phe)) of NM_000545.8. This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 28701371, internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID: 28701371, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, and PP4 cannot be applied (PMID:28701371, internal lab contributors). In summary, c.434C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PP3, PM1, PM2_Supporting, PS4_Moderate, PP1_Strong.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• PP1_Strong: This variant segregated with diabetes, with four informative meioses in two families with MODY (PMID: 28701371, internal lab contributors).
• PS4_Moderate: This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID:28701371, internal lab contributors).
• PP3: REVEL score: 0.989+10 deleterious predictors
• PM1: This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP.

Not Met criteria codes

• PP4: This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID:28701371, internal lab contributors).
• PM5: Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP.

Approved on: 2022-04-08

Published on: 2022-07-12