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.709A>C

CA386965448

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 420c4fb7-d35e-4074-b2fc-245b67fc9441

Approved on: 2021-12-30

Published on: 2021-12-30

HGVS expressions

NM_001306179.1:c.709A>C

NC_000012.12:g.120993702A>C

CM000674.2:g.120993702A>C

NC_000012.11:g.121431505A>C

CM000674.1:g.121431505A>C

NC_000012.10:g.119915888A>C

NG_011731.2:g.19957A>C

ENST00000257555.11:c.709A>C

ENST00000257555.10:c.709A>C

ENST00000400024.6:c.709A>C

ENST00000402929.5:n.844A>C

ENST00000535955.5:n.43-3789A>C

ENST00000538626.2:n.191-3789A>C

ENST00000538646.5:c.527-462A>C

ENST00000540108.1:c.*149A>C

ENST00000541395.5:c.709A>C

ENST00000541924.5:c.709A>C

ENST00000543427.5:c.633+76A>C

ENST00000544413.2:c.709A>C

ENST00000544574.5:c.73-2915A>C

ENST00000560968.5:n.852A>C

ENST00000615446.4:c.-257-2560A>C

ENST00000617366.4:c.586+123A>C

NM_000545.5:c.709A>C

NM_000545.6:c.709A>C

NM_000545.8:c.709A>C

NM_001306179.2:c.709A>C

Likely Pathogenic

PM2_Supporting PP3 PP4_Moderate PM5 PM1

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.709A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to histidine at codon 237 (p.(Asn237His)) of NM_000545.8. This variant is located within a conserved region of 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, the c.709A>C variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.816, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, (c.709A>G, p.Asn237Asp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). 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 sensitive) (PP4_Moderate; internal lab contributors). In summary, c.709A>C 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): PM1_Supporting, PM2_supporting, PM5_Supporting, PP4_Moderate, PP3

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.816 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45

PP4_Moderate

The N237H variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), who also responded to low dose sulfonylurea treatment.

PM5

The p.Asn237Asp variant has been interpreted as pathogenic by the MDEP.

PM1

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

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