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.485T>C (p.Leu162Pro)

CA386960483

447490 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5f553adc-686d-40f1-99d8-b5dd06f0b5ec

HGVS expressions

NM_000545.8:c.485T>C

NM_000545.8(HNF1A):c.485T>C (p.Leu162Pro)

NC_000012.12:g.120988991T>C

CM000674.2:g.120988991T>C

NC_000012.11:g.121426794T>C

CM000674.1:g.121426794T>C

NC_000012.10:g.119911177T>C

NG_011731.2:g.15246T>C

ENST00000257555.11:c.485T>C

ENST00000257555.10:c.485T>C

ENST00000400024.6:c.485T>C

ENST00000402929.5:n.620T>C

ENST00000535955.5:n.43-8500T>C

ENST00000538626.2:n.191-8500T>C

ENST00000538646.5:c.485T>C

ENST00000540108.1:c.327-4529T>C

ENST00000541395.5:c.485T>C

ENST00000541924.5:c.485T>C

ENST00000543427.5:c.485T>C

ENST00000544413.2:c.485T>C

ENST00000544574.5:c.73-7626T>C

ENST00000560968.5:n.628T>C

ENST00000615446.4:c.-257-7271T>C

ENST00000617366.4:c.485T>C

NM_000545.5:c.485T>C

NM_000545.6:c.485T>C

NM_001306179.1:c.485T>C

NM_001306179.2:c.485T>C

Uncertain Significance

PM1_Supporting PM2_Supporting PP3 PP4_Moderate

PS4

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.485T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 162 (p.(Leu162Pro)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, 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 persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21224407, internal lab contributors). In summary, c.485T>C 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 September 30, 2021): PP3, PM1_Supporting, PM2_supporting, PP4_Moderate.

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.

PM2_Supporting

This variant is absent from gnomAD.

PP3

REVEL 0.987 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score=4.9

PP4_Moderate

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 persistent C-peptide) (internal lab contributors).

PS4

This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21224407, internal lab contributors).

Approved on: 2022-04-09

Published on: 2022-07-12

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