Variant: NM_000545.8(HNF1A):c.1778G>C (p.Ser593Thr)

CA6832194

1687085 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: f2d10aa1-fc15-4407-a204-f231b59c9c22

Approved on: 2025-09-26

Published on: 2025-09-26

HGVS expressions

NM_000545.8:c.1778G>C
NM_000545.8(HNF1A):c.1778G>C (p.Ser593Thr)
NC_000012.12:g.121001074G>C
CM000674.2:g.121001074G>C
NC_000012.11:g.121438877G>C
CM000674.1:g.121438877G>C
NC_000012.10:g.119923260G>C
NG_011731.2:g.27329G>C
ENST00000560968.6:c.*525G>C
ENST00000257555.11:c.1778G>C
ENST00000257555.10:c.1778G>C
ENST00000288757.7:c.*3079C>G
ENST00000540108.1:c.*1218G>C
ENST00000541395.5:c.1871G>C
ENST00000543427.5:c.1241G>C
ENST00000544413.2:c.1799G>C
ENST00000560968.5:c.1595G>C
ENST00000615446.4:c.566G>C
ENST00000617366.4:c.*187G>C
NM_000545.5:c.1778G>C
NM_000545.6:c.1778G>C
NM_001306179.1:c.1799G>C
NM_001286191.2:c.*3079C>G
NM_001286196.2:c.*3079C>G
NM_001306179.2:c.1799G>C
NM_022895.3:c.*3079C>G

Uncertain Significance

• Not Met criteria codes: BS1 BP4 PP3 PP4 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 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1778G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 593 (p.(Ser593Thr)) of NM_000545.8. The Grpmax filtering allele frequency of the c.1778G>C variant in gnomAD v4.1.0 is 0.00003549, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. Additionally, this variant has a REVEL score of 0.3129, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to the age of diagnosis over 35 yo (internal lab contributors). In summary, c.1778G>A meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): None.

Not Met criteria codes

• BS1: The Grpmax filtering allele frequency of the c.1778G>C variant in gnomAD v4.1.0 is 0.00003257, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. gnomAD Popmax filtering AF = 0.00003257 < 0.000033
• BP4: REVEL = 0.3129
• PP3: REVEL = 0.3129
• PP4: This variant was identified in an individual(s) with diabetes; however, the MODY probability could not be calculated due to an age at diagnosis greater than 35 years (internal lab contributors).
• PM2: 0.00003549 in gnomAD ENF > 0.00002