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.396G>C

CA386959497

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 301fade0-c960-4402-b543-158b0ad0abbe

HGVS expressions

NM_001306179.2:c.396G>C

NC_000012.12:g.120988902G>C

CM000674.2:g.120988902G>C

NC_000012.11:g.121426705G>C

CM000674.1:g.121426705G>C

NC_000012.10:g.119911088G>C

NG_011731.2:g.15157G>C

ENST00000560968.6:c.396G>C

ENST00000257555.11:c.396G>C

ENST00000257555.10:c.396G>C

ENST00000400024.6:c.396G>C

ENST00000402929.5:n.531G>C

ENST00000535955.5:n.43-8589G>C

ENST00000538626.2:n.191-8589G>C

ENST00000538646.5:c.396G>C

ENST00000540108.1:c.327-4618G>C

ENST00000541395.5:c.396G>C

ENST00000541924.5:c.396G>C

ENST00000543427.5:c.396G>C

ENST00000544413.2:c.396G>C

ENST00000544574.5:c.73-7715G>C

ENST00000560968.5:c.539G>C

ENST00000615446.4:c.-257-7360G>C

ENST00000617366.4:c.396G>C

NM_000545.5:c.396G>C

NM_000545.6:c.396G>C

NM_001306179.1:c.396G>C

NM_000545.8:c.396G>C

Uncertain Significance

PM1 PM2_Supporting PM5_Supporting PP3

PS4 PP4

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 for HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.396G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to aspartic acid at codon 132 (p.(Glu132Asp)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.906, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.394G>A p.(Glu132Lys), has been classified as pathogenic by the ClinGen MDEP but has a higher grantham distance than p.(Glu132Asp) (PM5_Supporting). This variant was identified in 1 individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors). The MODY probability is unable to be calculated due to a lack of clinical information (internal lab contributors). In summary, c.390G>T 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 2.1.0, approved 8/11/2023): PM2_supporting, PM1, PP3, PM5_supporting.

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 (PM1).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.0.0, absent

PM5_Supporting

Another missense variant, c.394G>A p.(Glu132Lys), has been classified as pathogenic by the ClinGen MDEP but has a higher grantham distance than p.(Glu132Asp) (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.906, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PS4

This variant was identified in 1 individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors).

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (internal lab contributors).

Approved on: 2024-06-09

Published on: 2024-06-09

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