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_001306179.2:c.403G>A

CA386959579

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6d2f706b-4a36-4d7b-9e25-d02796bca96d

HGVS expressions

NM_001306179.2:c.403G>A

NC_000012.12:g.120988909G>A

CM000674.2:g.120988909G>A

NC_000012.11:g.121426712G>A

CM000674.1:g.121426712G>A

NC_000012.10:g.119911095G>A

NG_011731.2:g.15164G>A

ENST00000257555.11:c.403G>A

ENST00000257555.10:c.403G>A

ENST00000400024.6:c.403G>A

ENST00000402929.5:n.538G>A

ENST00000535955.5:n.43-8582G>A

ENST00000538626.2:n.191-8582G>A

ENST00000538646.5:c.403G>A

ENST00000540108.1:c.327-4611G>A

ENST00000541395.5:c.403G>A

ENST00000541924.5:c.403G>A

ENST00000543427.5:c.403G>A

ENST00000544413.2:c.403G>A

ENST00000544574.5:c.73-7708G>A

ENST00000560968.5:n.546G>A

ENST00000615446.4:c.-257-7353G>A

ENST00000617366.4:c.403G>A

NM_000545.5:c.403G>A

NM_000545.6:c.403G>A

NM_001306179.1:c.403G>A

NM_000545.8:c.403G>A

Uncertain Significance

PM1_Supporting PM2_Supporting PP3

PS4

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.403G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to asparagine at codon 135 (p.(Asp135Asn)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29207974, internal lab contributors). Additionally. the published case was stated to have antibody negative DM but not to meet classical diagnostic criteria for MODY. In summary, the c.403G>A variant 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 9/30/21): PP3, PM1_Supporting, PM2_Supporting.

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 (PM1_Supporting).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PS4

This variant was identified in two unrelated individuals with diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29207974, internal lab contributors). Additionally the published case was stated to have antibody negative DM but not to meet classical diagnostic criteria for MODY.

Approved on: 2022-07-01

Published on: 2022-07-01

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