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 label mismatch: HNF1A vs undefined
  • 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.281C>T (p.Pro94Leu)

CA214295

36816 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 02411569-0b5b-4f6a-9abd-8f9cfb0e9ac9
Approved on: 2025-06-27
Published on: 2025-06-27

HGVS expressions

NM_000545.8:c.281C>T
NM_000545.8(HNF1A):c.281C>T (p.Pro94Leu)
NC_000012.12:g.120979049C>T
CM000674.2:g.120979049C>T
NC_000012.11:g.121416852C>T
CM000674.1:g.121416852C>T
NC_000012.10:g.119901235C>T
NG_011731.2:g.5304C>T
ENST00000560968.6:c.281C>T
ENST00000257555.11:c.281C>T
ENST00000257555.10:c.281C>T
ENST00000400024.6:c.281C>T
ENST00000402929.5:n.416C>T
ENST00000535955.5:n.42+357C>T
ENST00000538626.2:n.190+209C>T
ENST00000538646.5:c.281C>T
ENST00000540108.1:c.281C>T
ENST00000541395.5:c.281C>T
ENST00000541924.5:c.281C>T
ENST00000543427.5:c.281C>T
ENST00000544413.2:c.281C>T
ENST00000544574.5:c.72+209C>T
ENST00000560968.5:c.424C>T
ENST00000615446.4:c.-258+338C>T
ENST00000617366.4:c.281C>T
NM_000545.5:c.281C>T
NM_000545.6:c.281C>T
NM_001306179.1:c.281C>T
NM_001306179.2:c.281C>T
More

Likely Pathogenic

Met criteria codes 4
PP3 PM2_Supporting PP1_Strong PP4_Moderate
Not Met criteria codes 1
PS4

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 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.281C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 94 (p.(Pro94Leu)) of NM_000545.8. This variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP threshold of 0.70 (PP3). Furthermore, this variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to sulfonylurea, antibody negative and persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 1 family (PP1_Strong; PMID: 27236918, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong.
Met criteria codes
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP threshold of 0.70 (PP3).
PM2_Supporting
This variant is absent from gnomAD v.2.1.1 (PM2_supporting). Absent in gnomAD v4.1.0.
PP1_Strong
This variant segregated with diabetes with 5 informative meioses in 1 family (PP1_Strong; PMID: 27236918, internal lab contributors).
PP4_Moderate
Tthis variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to sulfonylurea, antibody negative and persistent C-peptide) (PP4_Moderate; [internal lab contributors]).
Not Met criteria codes
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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