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.364T>C

CA386959120

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f20b7d10-69ff-4356-8bed-f07919d31a0a

HGVS expressions

NM_001306179.1:c.364T>C

NC_000012.12:g.120988870T>C

CM000674.2:g.120988870T>C

NC_000012.11:g.121426673T>C

CM000674.1:g.121426673T>C

NC_000012.10:g.119911056T>C

NG_011731.2:g.15125T>C

ENST00000257555.11:c.364T>C

ENST00000257555.10:c.364T>C

ENST00000400024.6:c.364T>C

ENST00000402929.5:n.499T>C

ENST00000535955.5:n.43-8621T>C

ENST00000538626.2:n.191-8621T>C

ENST00000538646.5:c.364T>C

ENST00000540108.1:c.327-4650T>C

ENST00000541395.5:c.364T>C

ENST00000541924.5:c.364T>C

ENST00000543427.5:c.364T>C

ENST00000544413.2:c.364T>C

ENST00000544574.5:c.73-7747T>C

ENST00000560968.5:n.507T>C

ENST00000615446.4:c.-257-7392T>C

ENST00000617366.4:c.364T>C

NM_000545.5:c.364T>C

NM_000545.6:c.364T>C

NM_000545.8:c.364T>C

NM_001306179.2:c.364T>C

Uncertain Significance

PM5_Supporting PP3 PM2_Supporting PM1_Supporting

PP4

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.364T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to histidine at codon 122 (p.(Tyr1223His)) 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.365A>G, p.Tyr122Cys, has been classified as likely pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.364T>C (PM5_Supporting). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50%, and therefore, PP4 was not applied (internal lab contributors). In summary, c.364T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3, PM5_Supporting.

PM5_Supporting

The c.365A>G p.(Tyr122Cys) variant has been interpreted as likely pathogenic by the MDEP.

PP3

REVEL = 0.971

PM2_Supporting

This variant is absent from gnomAD.

PM1_Supporting

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.

PP4

This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% (internal lab contributors).

Approved on: 2022-04-08

Published on: 2022-07-12

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