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
Curation History
JSON LD for Version 1.1

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

PS4 PP4_Moderate PP3 PP1_Strong PS3_Supporting PM2_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.

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).

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).

PP3

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

PP1_Strong

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

PS3_Supporting

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

PM2_Supporting

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

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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.