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.619G>T

CA386964418

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fb5299e2-08d5-4a29-9af4-2317f39b21ab

HGVS expressions

NM_001306179.2:c.619G>T

NC_000012.12:g.120993612G>T

CM000674.2:g.120993612G>T

NC_000012.11:g.121431415G>T

CM000674.1:g.121431415G>T

NC_000012.10:g.119915798G>T

NG_011731.2:g.19867G>T

ENST00000257555.11:c.619G>T

ENST00000257555.10:c.619G>T

ENST00000400024.6:c.619G>T

ENST00000402929.5:n.754G>T

ENST00000535955.5:n.43-3879G>T

ENST00000538626.2:n.191-3879G>T

ENST00000538646.5:c.527-552G>T

ENST00000540108.1:c.*59G>T

ENST00000541395.5:c.619G>T

ENST00000541924.5:c.619G>T

ENST00000543427.5:c.619G>T

ENST00000544413.2:c.619G>T

ENST00000544574.5:c.73-3005G>T

ENST00000560968.5:n.762G>T

ENST00000615446.4:c.-257-2650G>T

ENST00000617366.4:c.586+33G>T

NM_000545.5:c.619G>T

NM_000545.6:c.619G>T

NM_001306179.1:c.619G>T

NM_000545.8:c.619G>T

Likely Pathogenic

PM1_Supporting PP3 PM5 PM2_Supporting 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.619G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to cysteine at codon 207 (p.(Gly207Cys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.923, which is greater than the MDEP threshold of 0.70 (PP3). 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) (PP4_Moderate; internal lab contributor). Additionally, 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, another missense variant, c.620G>A p.(Gly207Asp) has been interpreted as pathogenic by the ClinGen MDEP and p.Gly207Cys has an equal or greater Grantham distance. (PM5). In summary, c.619G>T 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 9/30/2021): PP3, PP4_moderate, PM1_Supporting, PM2_Supporting, PM5.

PM1_Supporting

This variant is located within the DNA binding domain of HNF1A, which is critical for the protein’s function (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.923.

PM5

The [p.Gly207Asp] variant has been interpreted as pathogenic by the MDEP and [p.Gly207Cys] has a greater Grantham distance.

PM2_Supporting

This variant is absent from gnomAD (PM2_Supporting).

PP4_Moderate

This variant was identified in 1 individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A and negative antibodies).

Approved on: 2022-08-04

Published on: 2022-08-04

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