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]

Variant: NM_000545.8(HNF1A):c.55T>G (p.Ser19Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16619450

418252 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ea187211-5677-42da-b68c-3078ebc5cb77

Approved on: 2022-04-01

Published on: 2022-04-01

HGVS expressions

NM_000545.8:c.55T>G

NM_000545.8(HNF1A):c.55T>G (p.Ser19Ala)

NC_000012.12:g.120978823T>G

CM000674.2:g.120978823T>G

NC_000012.11:g.121416626T>G

CM000674.1:g.121416626T>G

NC_000012.10:g.119901009T>G

NG_011731.2:g.5078T>G

ENST00000257555.11:c.55T>G

ENST00000257555.10:c.55T>G

ENST00000400024.6:c.55T>G

ENST00000402929.5:n.190T>G

ENST00000535955.5:n.42+131T>G

ENST00000538626.2:n.173T>G

ENST00000538646.5:c.55T>G

ENST00000540108.1:c.55T>G

ENST00000541395.5:c.55T>G

ENST00000541924.5:c.55T>G

ENST00000543427.5:c.55T>G

ENST00000544413.2:c.55T>G

ENST00000544574.5:c.55T>G

ENST00000560968.5:n.198T>G

ENST00000615446.4:c.-258+112T>G

ENST00000617366.4:c.55T>G

NM_000545.5:c.55T>G

NM_000545.6:c.55T>G

NM_001306179.1:c.55T>G

NM_001306179.2:c.55T>G

Uncertain Significance

PM2_Supporting PP3 PM1

PM5

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.55T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to alanine at codon 19 (p.(Ser19Ala)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) 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 0.835, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.56C>T (p.Ser19Leu), has been classified by the ClinGen MDEP as a VUS; therefore, PM5 will not be applied. In summary, c.55T>G 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 1.0, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3.

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.835 + FATHMM/MetaSVM/MetalR/LRT/SIFT all predict deleterious effect

PM1

Variant occurs in the dimerization domain of HNF1A.

PM5

Another missense variant, c.56C>T (p.Ser19Leu), has been classified by the ClinGen MDEP as a VUS; therefore, PM5 will not be applied.

Curation History

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