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.392G>T (p.Arg131Leu)

CA386959454

447488 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8cd02eb2-ab8e-4166-b993-3e7866532520
Approved on: 2025-09-02
Published on: 2025-09-02

HGVS expressions

NM_000545.8:c.392G>T
NM_000545.8(HNF1A):c.392G>T (p.Arg131Leu)
NC_000012.12:g.120988898G>T
CM000674.2:g.120988898G>T
NC_000012.11:g.121426701G>T
CM000674.1:g.121426701G>T
NC_000012.10:g.119911084G>T
NG_011731.2:g.15153G>T
ENST00000560968.6:c.392G>T
ENST00000257555.11:c.392G>T
ENST00000257555.10:c.392G>T
ENST00000400024.6:c.392G>T
ENST00000402929.5:n.527G>T
ENST00000535955.5:n.43-8593G>T
ENST00000538626.2:n.191-8593G>T
ENST00000538646.5:c.392G>T
ENST00000540108.1:c.327-4622G>T
ENST00000541395.5:c.392G>T
ENST00000541924.5:c.392G>T
ENST00000543427.5:c.392G>T
ENST00000544413.2:c.392G>T
ENST00000544574.5:c.73-7719G>T
ENST00000560968.5:c.535G>T
ENST00000615446.4:c.-257-7364G>T
ENST00000617366.4:c.392G>T
NM_000545.5:c.392G>T
NM_000545.6:c.392G>T
NM_001306179.1:c.392G>T
NM_001306179.2:c.392G>T
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PP3 PM1 PM5_Strong
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 3.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.392G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 131 (p.(R131L)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.392G>A (p.Arg131Gln) and c.391C>T (p.Arg131Trp), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 447488). Taken together, this evidence supports the classification of this variant 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): PM5_Strong, PM1, PP3, PM2_Supporting.
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP threshold of 0.70 (PP3).
PM1
This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
PM5_Strong
Two other missense variants, c.392G>A (p.Arg131Gln) and c.391C>T (p.Arg131Trp), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong).
Not Met criteria codes
PS4
This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 447488).
Curation History
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