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.685C>G

CA386965163

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 254c7127-e408-415c-bf7b-92a8fc5443dd

HGVS expressions

NM_001306179.1:c.685C>G

NC_000012.12:g.120993678C>G

CM000674.2:g.120993678C>G

NC_000012.11:g.121431481C>G

CM000674.1:g.121431481C>G

NC_000012.10:g.119915864C>G

NG_011731.2:g.19933C>G

ENST00000257555.11:c.685C>G

ENST00000257555.10:c.685C>G

ENST00000400024.6:c.685C>G

ENST00000402929.5:n.820C>G

ENST00000535955.5:n.43-3813C>G

ENST00000538626.2:n.191-3813C>G

ENST00000538646.5:c.527-486C>G

ENST00000540108.1:c.*125C>G

ENST00000541395.5:c.685C>G

ENST00000541924.5:c.685C>G

ENST00000543427.5:c.633+52C>G

ENST00000544413.2:c.685C>G

ENST00000544574.5:c.73-2939C>G

ENST00000560968.5:n.828C>G

ENST00000615446.4:c.-257-2584C>G

ENST00000617366.4:c.586+99C>G

NM_000545.5:c.685C>G

NM_000545.6:c.685C>G

NM_000545.8:c.685C>G

NM_001306179.2:c.685C>G

Likely Pathogenic

PM2_Supporting PP3 PM5 PM1 PP4_Moderate

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.685C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 229 (p.(Arg229Gly)) of NM_000545.6. This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), one of whom also responded to low dose sulfonylurea treatment (PP4_Moderate; internal laboratory contributor). This variant is located within the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Two other missense variants, c.686G>A(p.(Arg229Gln)) and c.686G>C (p.(Arg229Pro), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Finally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). In summary, c.685C>G 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 6/4/2021): (PP4_Moderate, PM1_Supporting, PM5_Strong, PM2_Supporting, PP3).

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.903 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45

PM5

The p.Arg229Gln variant has been interpreted as pathogenic by the MDEP.

PM1

This variant is located within the DNA binding domain of HNF1A, which is critical for the protein’s function.

PP4_Moderate

This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), one of whom also responded to low dose sulfonylurea treatment.

Approved on: 2021-12-30

Published on: 2021-12-30

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