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_000545.8(HNF1A):c.710A>C (p.Asn237Thr)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386965452

447497 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4fb2d455-dbd0-4b5d-bbdf-3e3741faa326

Approved on: 2022-04-12

Published on: 2022-07-12

HGVS expressions

NM_000545.8:c.710A>C

NM_000545.8(HNF1A):c.710A>C (p.Asn237Thr)

NC_000012.12:g.120993703A>C

CM000674.2:g.120993703A>C

NC_000012.11:g.121431506A>C

CM000674.1:g.121431506A>C

NC_000012.10:g.119915889A>C

NG_011731.2:g.19958A>C

ENST00000257555.11:c.710A>C

ENST00000257555.10:c.710A>C

ENST00000400024.6:c.710A>C

ENST00000402929.5:n.845A>C

ENST00000535955.5:n.43-3788A>C

ENST00000538626.2:n.191-3788A>C

ENST00000538646.5:c.527-461A>C

ENST00000540108.1:c.*150A>C

ENST00000541395.5:c.710A>C

ENST00000541924.5:c.710A>C

ENST00000543427.5:c.633+77A>C

ENST00000544413.2:c.710A>C

ENST00000544574.5:c.73-2914A>C

ENST00000560968.5:n.853A>C

ENST00000615446.4:c.-257-2559A>C

ENST00000617366.4:c.586+124A>C

NM_000545.5:c.710A>C

NM_000545.6:c.710A>C

NM_001306179.1:c.710A>C

NM_001306179.2:c.710A>C

Uncertain Significance

PM1_Supporting PM2_Supporting PP3 PM5_Supporting

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.710A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to threonine at codon 237 (p.(Asn237Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.888, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.709A>G (p.Asn237Asp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.710A>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 September 30, 2021): PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3.

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.888 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45

PM5_Supporting

The p.Asn237Asp variant has been interpreted as likely pathogenic by the MDEP.

Curation History

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