Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000545.8(HNF1A):c.29C>T (p.Thr10Met)

CA6831654

435422 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ef86fda-d3aa-499f-b2c7-b048f46262cb
Approved on: 2025-11-26
Published on: 2025-11-26

HGVS expressions

NM_000545.8:c.29C>T
NM_000545.8(HNF1A):c.29C>T (p.Thr10Met)
NC_000012.12:g.120978797C>T
CM000674.2:g.120978797C>T
NC_000012.11:g.121416600C>T
CM000674.1:g.121416600C>T
NC_000012.10:g.119900983C>T
NG_011731.2:g.5052C>T
ENST00000560968.6:c.29C>T
ENST00000257555.11:c.29C>T
ENST00000257555.10:c.29C>T
ENST00000400024.6:c.29C>T
ENST00000402929.5:n.164C>T
ENST00000535955.5:n.42+105C>T
ENST00000538626.2:n.147C>T
ENST00000538646.5:c.29C>T
ENST00000540108.1:c.29C>T
ENST00000541395.5:c.29C>T
ENST00000541924.5:c.29C>T
ENST00000543427.5:c.29C>T
ENST00000544413.2:c.29C>T
ENST00000544574.5:c.29C>T
ENST00000560968.5:c.172C>T
ENST00000615446.4:c.-258+86C>T
ENST00000617366.4:c.29C>T
NM_000545.5:c.29C>T
NM_000545.6:c.29C>T
NM_001306179.1:c.29C>T
NM_001306179.2:c.29C>T
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Uncertain Significance

Met criteria codes 4
PM5_Supporting BS1 PP4 PM1_Supporting
Not Met criteria codes 5
BP4 PS4 PM2 BA1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.00003472 in gnomAD v4.1.0, which is above the ClinGen MDEP threshold for BS1 (≥0.000033). This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (PMID: 30155490, 18003757, internal lab contributors). Another missense variant at the same residue, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, the c.29C>T variant 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): BS1, PM1_Supporting, PP4, PM5_Suppporting.
Met criteria codes
PM5_Supporting
Another missense variant at the same residue, c.28A>C (p.Thr10Pro), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
BS1
This variant has a Grpmax filtering allele frequency of 0.00003472 in gnomAD v4.1.0, which is above the ClinGen MDEP threshold for BS1 (≥0.000033).
PP4
Patient MODY probability calculator score >50% and HNF4A-variant negative
PM1_Supporting
In the dimerization domain (codons 1-32)
Not Met criteria codes
BP4
This variant has a REVEL score of 0.634, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact onHNF1A function.
PS4
At least 5 unrelated cases with with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant MAF in gnomAD 4.1.0 is above the MDEP PM2_Supporting cutoff.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
This variant has a REVEL score of 0.634, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact onHNF1A function.
Curation History
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