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]

Variant: NM_000545.6(HNF1A):c.1A>T (p.Met1Leu)

CA386951973

502525 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9119b620-1951-443c-96fd-5a29455f8200
Approved on: 2022-03-04
Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.1A>T
NM_000545.6(HNF1A):c.1A>T (p.Met1Leu)
NC_000012.12:g.120978769A>T
CM000674.2:g.120978769A>T
NC_000012.11:g.121416572A>T
CM000674.1:g.121416572A>T
NC_000012.10:g.119900955A>T
NG_011731.2:g.5024A>T
ENST00000257555.11:c.1A>T
ENST00000257555.10:c.1A>T
ENST00000400024.6:c.1A>T
ENST00000402929.5:n.136A>T
ENST00000535955.5:n.42+77A>T
ENST00000538626.2:n.119A>T
ENST00000538646.5:c.1A>T
ENST00000540108.1:c.1A>T
ENST00000541395.5:c.1A>T
ENST00000541924.5:c.1A>T
ENST00000543427.5:c.1A>T
ENST00000544413.2:c.1A>T
ENST00000544574.5:c.1A>T
ENST00000560968.5:n.144A>T
ENST00000615446.4:c.-258+58A>T
ENST00000617366.4:c.1A>T
NM_000545.5:c.1A>T
NM_001306179.1:c.1A>T
NM_000545.8:c.1A>T
NM_001306179.2:c.1A>T
NM_000545.8(HNF1A):c.1A>T (p.Met1Leu)
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Pathogenic

Met criteria codes 3
PP4_Moderate PM2_Supporting PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.1A>T variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Leu) of transcript NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting and PP4_Moderate.
Met criteria codes
PP4_Moderate
This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), who was also antibody negative.
PM2_Supporting
This variant is absent from gnomAD.
PVS1
A transcript with this variant is predicted to cause loss of function and result in nonsense mediated decay of a biologically relevant exon.
Curation History
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