Variant: NM_000545.8(HNF1A):c.1592G>C (p.Ser531Thr)

CA124484

14947 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4f7ac8c9-461a-4699-8865-f7a70c062ed4

Approved on: 2025-11-26

Published on: 2025-11-26

HGVS expressions

NM_000545.8:c.1592G>C
NM_000545.8(HNF1A):c.1592G>C (p.Ser531Thr)
NC_000012.12:g.120999358G>C
CM000674.2:g.120999358G>C
NC_000012.11:g.121437161G>C
CM000674.1:g.121437161G>C
NC_000012.10:g.119921544G>C
NG_011731.2:g.25613G>C
ENST00000560968.6:c.*339G>C
ENST00000257555.11:c.1592G>C
ENST00000257555.10:c.1592G>C
ENST00000540108.1:c.*1032G>C
ENST00000541395.5:c.1592G>C
ENST00000543427.5:c.1055G>C
ENST00000544413.2:c.1592G>C
ENST00000560968.5:c.1409G>C
ENST00000615446.4:c.380G>C
ENST00000617366.4:c.*1G>C
NM_000545.5:c.1592G>C
NM_000545.6:c.1592G>C
NM_001306179.1:c.1592G>C
NM_001306179.2:c.1592G>C

Uncertain Significance

• Not Met criteria codes: BS1 BS4 BP4 PS4 PP4 PP3 PM2

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 3.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1592G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 531 (p.(Ser531Thr)) of NM_000545.8. The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.000004290, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.62, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in five unrelated individuals with diabetes; however, PS4_Moderate does not apply because the variant is above the PM2_Supporting threshold and PP4 cannot be applied due to lack of clinical information (internal lab contributors). This variant does not appear to segregate with diabetes in a family (internal lab contributors), but the MODY probability was unable to be calculated in family members without the variant due to lack of clinical information. In summary, c.1592G>C 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 3.1.0, approved 10/10/2025): none.

Not Met criteria codes

• BS1: The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.000004290, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
• BS4: This variant does not appear to segregate with diabetes in a family (internal lab contributors), but the MODY probability was unable to be calculated in family members without the variant due to lack of clinical information.
• BP4: This variant has a REVEL score of 0.62, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function.
• PS4: PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff.
• PP4: This variant was identified individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (internal lab contributors).
• PP3: This variant has a REVEL score of 0.62, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function.
• PM2: The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.000004290, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.