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]

Variant: NM_000545.8(HNF1A):c.599G>A (p.Arg200Gln)

Curation Version - 1.1
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CA16606474

381588 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3494780c-5e33-4e9a-bd0b-b8754e5d04e1

Approved on: 2022-04-10

Published on: 2022-07-12

HGVS expressions

NM_000545.8:c.599G>A

NM_000545.8(HNF1A):c.599G>A (p.Arg200Gln)

NC_000012.12:g.120993592G>A

CM000674.2:g.120993592G>A

NC_000012.11:g.121431395G>A

CM000674.1:g.121431395G>A

NC_000012.10:g.119915778G>A

NG_011731.2:g.19847G>A

ENST00000257555.11:c.599G>A

ENST00000257555.10:c.599G>A

ENST00000400024.6:c.599G>A

ENST00000402929.5:n.734G>A

ENST00000535955.5:n.43-3899G>A

ENST00000538626.2:n.191-3899G>A

ENST00000538646.5:c.527-572G>A

ENST00000540108.1:c.*39G>A

ENST00000541395.5:c.599G>A

ENST00000541924.5:c.599G>A

ENST00000543427.5:c.599G>A

ENST00000544413.2:c.599G>A

ENST00000544574.5:c.73-3025G>A

ENST00000560968.5:n.742G>A

ENST00000615446.4:c.-257-2670G>A

ENST00000617366.4:c.586+13G>A

NM_000545.5:c.599G>A

NM_000545.6:c.599G>A

NM_001306179.1:c.599G>A

NM_001306179.2:c.599G>A

Pathogenic

PP4_Moderate PP1_Strong PS4 PP3 PM2_Supporting PS3_Supporting

PM5

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.599G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 200 (p.(Arg200Gln)) of transcript, e.g. NM_000545.8. This variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.926, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 23517481; internal lab contributors). Functional studies demonstrated the p.Arg200Gln protein has transactivation 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 15522234). Lastly, this variant was identified in at least three individuals from one family with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.599G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PP3, PM2_Supporting, PS3_Supporting, PS4, PP4_Moderate.

PP4_Moderate

The R200Q variant was identified in three individuals in one family with a clinical history highly specific HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (internal lab contributors).

PP1_Strong

This variant segregated with disease with 11 informative meioses in six families with MODY.

PS4

This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID: 23517481, internal lab contributors).

PP3

REVEL 0.926 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.55

PM2_Supporting

This variant is absent from the gnomAD European non-Finnish population and only one copy is present in the Latino population.

PS3_Supporting

Functional studies demonstrated the p.Arg200Gln protein has transactivation 40% of wildtype, indicating that this variant impacts protein function (PMID: 15522234).

PM5

Another missense variant, c598C>T (p.Arg200Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg200Gln, and p.Arg200Gln was used to apply PM5 to p.Arg200Trp.

Curation History

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