Variant: NM_000545.6(HNF1A):c.803T>C (p.Phe268Ser)

CA214330

36831 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 6fcf1304-1a2d-416e-9805-3e69f6fdd22a

Approved on: 2025-08-05

Published on: 2025-08-05

HGVS expressions

NM_000545.6:c.803T>C
NM_000545.6(HNF1A):c.803T>C (p.Phe268Ser)
NC_000012.12:g.120994253T>C
CM000674.2:g.120994253T>C
NC_000012.11:g.121432056T>C
CM000674.1:g.121432056T>C
NC_000012.10:g.119916439T>C
NG_011731.2:g.20508T>C
ENST00000560968.6:c.750+53T>C
ENST00000257555.11:c.803T>C
ENST00000257555.10:c.803T>C
ENST00000400024.6:c.803T>C
ENST00000402929.5:n.938T>C
ENST00000535955.5:n.43-3238T>C
ENST00000538626.2:n.191-3238T>C
ENST00000538646.5:c.616T>C
ENST00000540108.1:c.*243T>C
ENST00000541395.5:c.803T>C
ENST00000541924.5:c.713+547T>C
ENST00000543427.5:c.633+627T>C
ENST00000544413.2:c.803T>C
ENST00000544574.5:c.73-2364T>C
ENST00000560968.5:c.893+53T>C
ENST00000615446.4:c.-257-2009T>C
ENST00000617366.4:c.586+674T>C
NM_000545.5:c.803T>C
NM_001306179.1:c.803T>C
NM_000545.8:c.803T>C
NM_001306179.2:c.803T>C

Likely Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PM1_Supporting PP3 PS2_Moderate

• Not Met criteria codes: PP1 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 for HNF1A Version 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 15305805). One of these individuals did have a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, so PP4 cannot be applied (internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile)​ and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PS2_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting.

Met criteria codes

• PS4_Moderate: This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting).
• PM1_Supporting: This variant is located within the DNA binding domain of HNF1A (codons 201-280), 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 0.986, which is greater than the MDEP threshold of 0.70 (PP3).
• PS2_Moderate: This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor).

Not Met criteria codes

• PP1: This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 15305805).
• PP4: This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors).
• PM5: Two other missense variants, c.802T>A p.(Phe268Ile)​ and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied.