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_001306179.1:c.607C>A

CA386964227

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1e39313d-274c-4dd8-9980-3d01757db440

HGVS expressions

NM_001306179.1:c.607C>A

NC_000012.12:g.120993600C>A

CM000674.2:g.120993600C>A

NC_000012.11:g.121431403C>A

CM000674.1:g.121431403C>A

NC_000012.10:g.119915786C>A

NG_011731.2:g.19855C>A

ENST00000257555.11:c.607C>A

ENST00000257555.10:c.607C>A

ENST00000400024.6:c.607C>A

ENST00000402929.5:n.742C>A

ENST00000535955.5:n.43-3891C>A

ENST00000538626.2:n.191-3891C>A

ENST00000538646.5:c.527-564C>A

ENST00000540108.1:c.*47C>A

ENST00000541395.5:c.607C>A

ENST00000541924.5:c.607C>A

ENST00000543427.5:c.607C>A

ENST00000544413.2:c.607C>A

ENST00000544574.5:c.73-3017C>A

ENST00000560968.5:n.750C>A

ENST00000615446.4:c.-257-2662C>A

ENST00000617366.4:c.586+21C>A

NM_000545.5:c.607C>A

NM_000545.6:c.607C>A

NM_000545.8:c.607C>A

NM_001306179.2:c.607C>A

Pathogenic

PM2_Supporting PP3 PM1 PM5_Strong PP4_Moderate

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.607C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 203 (p.(Arg203Ser)) 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), and is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.607C>T (p.Arg203Cys) and c.608G>A (p.Arg203His),have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg203Ser has a greater Grantham distance than p.Arg203His (PM5_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.876, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, 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 response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.607C>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 9/30/21): PM1, PM2_Supporting, PP3, PM5_Strong, PP4_Moderate.

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.876 + DANN, GERP, FATHMM, LRT, 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.

PM5_Strong

Two other missense variants, c.607C>T (p.Arg203Cys) and c.608G>A (p.Arg203His),have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg203Ser has a greater Grantham distance than p.Arg203His.

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 sulfonylurea-responsive).

Approved on: 2022-04-11

Published on: 2022-07-12

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