Variant: NM_000545.6(HNF1A):c.670C>T (p.Pro224Ser)

CA214317

36826 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: e586f251-a3d4-479a-8235-73e932704a5b

Approved on: 2021-12-30

Published on: 2021-12-30

HGVS expressions

NM_000545.6:c.670C>T
NM_000545.6(HNF1A):c.670C>T (p.Pro224Ser)
NC_000012.12:g.120993663C>T
CM000674.2:g.120993663C>T
NC_000012.11:g.121431466C>T
CM000674.1:g.121431466C>T
NC_000012.10:g.119915849C>T
NG_011731.2:g.19918C>T
ENST00000257555.11:c.670C>T
ENST00000257555.10:c.670C>T
ENST00000400024.6:c.670C>T
ENST00000402929.5:n.805C>T
ENST00000535955.5:n.43-3828C>T
ENST00000538626.2:n.191-3828C>T
ENST00000538646.5:c.527-501C>T
ENST00000540108.1:c.*110C>T
ENST00000541395.5:c.670C>T
ENST00000541924.5:c.670C>T
ENST00000543427.5:c.633+37C>T
ENST00000544413.2:c.670C>T
ENST00000544574.5:c.73-2954C>T
ENST00000560968.5:n.813C>T
ENST00000615446.4:c.-257-2599C>T
ENST00000617366.4:c.586+84C>T
NM_000545.5:c.670C>T
NM_001306179.1:c.670C>T
NM_000545.8:c.670C>T
NM_001306179.2:c.670C>T
NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser)

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Pathogenic"

• Met criteria codes: PP1_Strong PP4_Moderate PM2_Supporting PP3 PM1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID: 15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). 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 contributors). Additionally, 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). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>T 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 June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting

Met criteria codes

• PP1_Strong: The P224S variant segregated with disease with four informative meioses in three families with MODY.
• PP4_Moderate: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), who also responded to lose dose sulfonylureas.
• PM2_Supporting: This variant is absent from gnomAD.
• PP3: REVEL 0.944+ FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45​
• PM1: This variant is located within the DNA binding domain of HNF1A, which is critical for the protein's function.