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_000545.5(HNF1A):c.598C>T (p.Arg200Trp)

CA214311

36824 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 12591884-428f-498d-95c2-6e7b98985cdf

Approved on: 2022-04-10

Published on: 2022-07-12

HGVS expressions

NM_000545.5(HNF1A):c.598C>T (p.Arg200Trp)

NC_000012.12:g.120993591C>T

CM000674.2:g.120993591C>T

NC_000012.11:g.121431394C>T

CM000674.1:g.121431394C>T

NC_000012.10:g.119915777C>T

NG_011731.2:g.19846C>T

ENST00000257555.11:c.598C>T

ENST00000257555.10:c.598C>T

ENST00000400024.6:c.598C>T

ENST00000402929.5:n.733C>T

ENST00000535955.5:n.43-3900C>T

ENST00000538626.2:n.191-3900C>T

ENST00000538646.5:c.527-573C>T

ENST00000540108.1:c.*38C>T

ENST00000541395.5:c.598C>T

ENST00000541924.5:c.598C>T

ENST00000543427.5:c.598C>T

ENST00000544413.2:c.598C>T

ENST00000544574.5:c.73-3026C>T

ENST00000560968.5:n.741C>T

ENST00000615446.4:c.-257-2671C>T

ENST00000617366.4:c.586+12C>T

NM_000545.5:c.598C>T

NM_000545.6:c.598C>T

NM_001306179.1:c.598C>T

NM_000545.8:c.598C>T

NM_001306179.2:c.598C>T

Pathogenic

PP3 PM5 PS4 PP4_Moderate PM2_Supporting PP1_Strong

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.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). 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, and negative autoantibodies) (PP4_Moderate; PMID: 32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>T 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, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5.

PP3

REVEL 0.775 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.55

PM5

Another missense variant, c.599G>A (p.Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trip has a greater Grantham distance (PM5).

PS4

This variant was identified in ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 29927023, 9754819, 17440016, 32238361, internal lab contributors).

PP4_Moderate

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, and negative antibodies) (PMID: 32238361).

PM2_Supporting

This variant is absent from gnomAD.

PP1_Strong

This variant segregated with disease with five informative meioses in five families with MODY.

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