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.616T>A (p.Trp206Arg)

CA16609261

393434 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8bdb1080-f9e5-4bab-83e2-28a709bdcb9b

HGVS expressions

NM_000545.8:c.616T>A

NM_000545.8(HNF1A):c.616T>A (p.Trp206Arg)

NC_000012.12:g.120993609T>A

CM000674.2:g.120993609T>A

NC_000012.11:g.121431412T>A

CM000674.1:g.121431412T>A

NC_000012.10:g.119915795T>A

NG_011731.2:g.19864T>A

ENST00000257555.11:c.616T>A

ENST00000257555.10:c.616T>A

ENST00000400024.6:c.616T>A

ENST00000402929.5:n.751T>A

ENST00000535955.5:n.43-3882T>A

ENST00000538626.2:n.191-3882T>A

ENST00000538646.5:c.527-555T>A

ENST00000540108.1:c.*56T>A

ENST00000541395.5:c.616T>A

ENST00000541924.5:c.616T>A

ENST00000543427.5:c.616T>A

ENST00000544413.2:c.616T>A

ENST00000544574.5:c.73-3008T>A

ENST00000560968.5:n.759T>A

ENST00000615446.4:c.-257-2653T>A

ENST00000617366.4:c.586+30T>A

NM_000545.5:c.616T>A

NM_000545.6:c.616T>A

NM_001306179.1:c.616T>A

NM_001306179.2:c.616T>A

Likely Pathogenic

PP3 PM1 PM2_Supporting PP4_Moderate

PS4 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.616T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tryptophan to arginine at codon 206 (p.(Trp206Arg)) of NM_000545.8. 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.899, 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, negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified in two unrelated individuals 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 (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.616T>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 September 30, 2021): PM1, PM2_Supporting, PP3, PP4_Moderate.

PP3

REVEL 0.899 + GERP, FATHMM, LRT, MetaLR, MetaSVM, MutationAssessor, MutationTaster, PROVEAN and SIFT all predict deleterious

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.

PM2_Supporting

This variant is absent from gnomAD.

PP4_Moderate

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, and negative antibodies).

PS4

This variant was identified in two unrelated individuals 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 (internal lab contributors).

PP1

This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).

Approved on: 2022-04-11

Published on: 2022-07-12

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