Evidence Repository - Clinical Genome Resources

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.817A>C (p.Lys273Gln)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386966376

447504 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d1d6fbcd-1b79-4402-b925-fef6d907641f

Approved on: 2022-04-15

Published on: 2022-07-12

HGVS expressions

NM_000545.6:c.817A>C

NM_000545.6(HNF1A):c.817A>C (p.Lys273Gln)

NC_000012.12:g.120994267A>C

CM000674.2:g.120994267A>C

NC_000012.11:g.121432070A>C

CM000674.1:g.121432070A>C

NC_000012.10:g.119916453A>C

NG_011731.2:g.20522A>C

ENST00000257555.11:c.817A>C

ENST00000257555.10:c.817A>C

ENST00000400024.6:c.817A>C

ENST00000402929.5:n.952A>C

ENST00000535955.5:n.43-3224A>C

ENST00000538626.2:n.191-3224A>C

ENST00000538646.5:c.630A>C

ENST00000540108.1:c.*257A>C

ENST00000541395.5:c.817A>C

ENST00000541924.5:c.713+561A>C

ENST00000543427.5:c.633+641A>C

ENST00000544413.2:c.817A>C

ENST00000544574.5:c.73-2350A>C

ENST00000560968.5:n.893+67A>C

ENST00000615446.4:c.-257-1995A>C

ENST00000617366.4:c.586+688A>C

NM_000545.5:c.817A>C

NM_001306179.1:c.817A>C

NM_000545.8:c.817A>C

NM_001306179.2:c.817A>C

NM_000545.8(HNF1A):c.817A>C (p.Lys273Gln)

Uncertain Significance

PM2_Supporting PP3 PM1

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.817A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamine at codon 273 (p.(Lys273Gln) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, 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 absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.817A>C 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 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3.

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.817 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said low, GERP score 4.84

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.

Curation History

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