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_000545.8(HNF1A):c.760C>A (p.Leu254Met)

CA386965972

1334147 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8faddaea-f0a3-484b-8c21-a78ed82fb55d

HGVS expressions

NM_000545.8:c.760C>A

NM_000545.8(HNF1A):c.760C>A (p.Leu254Met)

NC_000012.12:g.120994210C>A

CM000674.2:g.120994210C>A

NC_000012.11:g.121432013C>A

CM000674.1:g.121432013C>A

NC_000012.10:g.119916396C>A

NG_011731.2:g.20465C>A

ENST00000257555.11:c.760C>A

ENST00000257555.10:c.760C>A

ENST00000400024.6:c.760C>A

ENST00000402929.5:n.895C>A

ENST00000535955.5:n.43-3281C>A

ENST00000538626.2:n.191-3281C>A

ENST00000538646.5:c.573C>A

ENST00000540108.1:c.*200C>A

ENST00000541395.5:c.760C>A

ENST00000541924.5:c.713+504C>A

ENST00000543427.5:c.633+584C>A

ENST00000544413.2:c.760C>A

ENST00000544574.5:c.73-2407C>A

ENST00000560968.5:n.893+10C>A

ENST00000615446.4:c.-257-2052C>A

ENST00000617366.4:c.586+631C>A

NM_000545.5:c.760C>A

NM_000545.6:c.760C>A

NM_001306179.1:c.760C>A

NM_001306179.2:c.760C>A

Uncertain Significance

PM1_Supporting PP3 PM2_Supporting

PS4 PP4 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.760C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Leucine to Methionine at codon 254 (p.(Leu254Met)) of NM_000545.8. This variant is located within the DNA binding of HNF1A, which is critical for the protein’s function (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.799 (PP3). The variant was identified in 2 individuals with diabetes, however this number does not meet the MDEP cutoff for PS4_Supporting. The MODY probability is unable to be calculated for these individuals due to lack of clinical information (PMIDs: 11942313, 9287055). Another missense variant, c.761T>A p.Leu254Gln, has been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.760C>A meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/21): PM2_Supporting, PM1, PP3.

PM1_Supporting

This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP.

PP3

REVEL 0.799

PM2_Supporting

absent gnomAD

PS4

2 probands

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMIDs: 11942313, 9287055).

PM5

Another missense variant, c.761T>A p.Leu254Gln, has been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2022-04-21

Published on: 2022-04-21

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