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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.1:c.490A>C

CA386960511

1317072 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 192f4578-ad75-4488-94fc-ac36f978dc8a

HGVS expressions

NM_001306179.1:c.490A>C

NC_000012.12:g.120988996A>C

CM000674.2:g.120988996A>C

NC_000012.11:g.121426799A>C

CM000674.1:g.121426799A>C

NC_000012.10:g.119911182A>C

NG_011731.2:g.15251A>C

ENST00000257555.11:c.490A>C

ENST00000257555.10:c.490A>C

ENST00000400024.6:c.490A>C

ENST00000402929.5:n.625A>C

ENST00000535955.5:n.43-8495A>C

ENST00000538626.2:n.191-8495A>C

ENST00000538646.5:c.490A>C

ENST00000540108.1:c.327-4524A>C

ENST00000541395.5:c.490A>C

ENST00000541924.5:c.490A>C

ENST00000543427.5:c.490A>C

ENST00000544413.2:c.490A>C

ENST00000544574.5:c.73-7621A>C

ENST00000560968.5:n.633A>C

ENST00000615446.4:c.-257-7266A>C

ENST00000617366.4:c.490A>C

NM_000545.5:c.490A>C

NM_000545.6:c.490A>C

NM_000545.8:c.490A>C

NM_001306179.2:c.490A>C

NM_000545.8(HNF1A):c.490A>C (p.Thr164Pro)

Uncertain Significance

PM1_Supporting PP4_Moderate PP3 PM2_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.490A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to proline at codon 164 (p.(Thr164Pro)) 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 0.944, which is greater than the MDEP threshold of 0.70 (PP3). 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) who was also antibody negative (PP4_Moderate; internal lab contributors). In summary, c.490A>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, PM2_Supporting, PP3, PP4_Moderate.

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.

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.

PP3

REVEL 0.944 + DANN, GERP, FATHMM, LRT, MutationAssessor, MutationTaster, PROVEAN and SIFT all predict deleterious

PM2_Supporting

This variant is absent from gnomAD.

Approved on: 2022-04-10

Published on: 2022-07-12

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