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_001306179.2:c.781G>A

CA386966092

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0e58f20e-3d68-4996-ae8d-cb99d8653f95

HGVS expressions

NM_001306179.2:c.781G>A

NC_000012.12:g.120994231G>A

CM000674.2:g.120994231G>A

NC_000012.11:g.121432034G>A

CM000674.1:g.121432034G>A

NC_000012.10:g.119916417G>A

NG_011731.2:g.20486G>A

ENST00000257555.11:c.781G>A

ENST00000257555.10:c.781G>A

ENST00000400024.6:c.781G>A

ENST00000402929.5:n.916G>A

ENST00000535955.5:n.43-3260G>A

ENST00000538626.2:n.191-3260G>A

ENST00000538646.5:c.594G>A

ENST00000540108.1:c.*221G>A

ENST00000541395.5:c.781G>A

ENST00000541924.5:c.713+525G>A

ENST00000543427.5:c.633+605G>A

ENST00000544413.2:c.781G>A

ENST00000544574.5:c.73-2386G>A

ENST00000560968.5:n.893+31G>A

ENST00000615446.4:c.-257-2031G>A

ENST00000617366.4:c.586+652G>A

NM_000545.5:c.781G>A

NM_000545.6:c.781G>A

NM_001306179.1:c.781G>A

NM_000545.8:c.781G>A

Likely Pathogenic

PP4 PP3 PM2_Supporting PP1_Strong PM1_Supporting

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.781G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 261 (p.(Glu261Lys)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID:16917892, internal lab contributor). This variant segregated with diabetes, with five informative meioses in this individual's family (PP1_Strong; internal lab contributor). Taken together, this evidence supports the classification of c.781G>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 8/18/21): PP1_Strong, PP3, PP4, PM1_Supporting, PM2_Supporting.

PP4

This variant was identified in an inidividual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID:16917892, internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP threshold of 0.70 (PP3).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP1_Strong

This variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; internal lab contributor).

PM1_Supporting

This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

Approved on: 2021-08-24

Published on: 2021-10-29

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