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_000545.8(HNF1A):c.626C>A (p.Ala209Glu)

CA386964506

586794 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c0152b3d-4ecf-4235-8d8a-9d4f8c160a86

HGVS expressions

NM_000545.8:c.626C>A

NM_000545.8(HNF1A):c.626C>A (p.Ala209Glu)

NC_000012.12:g.120993619C>A

CM000674.2:g.120993619C>A

NC_000012.11:g.121431422C>A

CM000674.1:g.121431422C>A

NC_000012.10:g.119915805C>A

NG_011731.2:g.19874C>A

ENST00000257555.11:c.626C>A

ENST00000257555.10:c.626C>A

ENST00000400024.6:c.626C>A

ENST00000402929.5:n.761C>A

ENST00000535955.5:n.43-3872C>A

ENST00000538626.2:n.191-3872C>A

ENST00000538646.5:c.527-545C>A

ENST00000540108.1:c.*66C>A

ENST00000541395.5:c.626C>A

ENST00000541924.5:c.626C>A

ENST00000543427.5:c.626C>A

ENST00000544413.2:c.626C>A

ENST00000544574.5:c.73-2998C>A

ENST00000560968.5:n.769C>A

ENST00000615446.4:c.-257-2643C>A

ENST00000617366.4:c.586+40C>A

NM_000545.5:c.626C>A

NM_000545.6:c.626C>A

NM_001306179.1:c.626C>A

NM_001306179.2:c.626C>A

Likely Pathogenic

PS4_Moderate PM1_Supporting PP4 PP3 PM2_Supporting

PP1

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.626C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glutamic acid at codon 209 (p.(Ala209Glu)) 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). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.626C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting.

PS4_Moderate

This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors).

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).

PP4

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

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

PP1

1 meosis in a family with non-autoimmune diabetes

Approved on: 2022-07-01

Published on: 2022-07-01

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