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_175914.5(HNF4A):c.740T>C (p.Leu247Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409107461

435438 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5de1a645-18f5-499a-a7bc-fffefe65af24

Approved on: 2024-08-30

Published on: 2024-08-30

HGVS expressions

NM_175914.5:c.740T>C

NM_175914.5(HNF4A):c.740T>C (p.Leu247Pro)

NC_000020.11:g.44419790T>C

CM000682.2:g.44419790T>C

NC_000020.10:g.43048430T>C

CM000682.1:g.43048430T>C

NC_000020.9:g.42481844T>C

NG_009818.1:g.68990T>C

ENST00000316673.9:c.740T>C

ENST00000316099.10:c.806T>C

ENST00000619550.5:c.780T>C

ENST00000683148.1:n.782T>C

ENST00000683657.1:n.1930T>C

ENST00000316099.9:c.806T>C

ENST00000316099.8:c.806T>C

ENST00000316673.8:c.740T>C

ENST00000372920.1:c.*573T>C

ENST00000415691.2:c.806T>C

ENST00000443598.6:c.806T>C

ENST00000457232.5:c.740T>C

ENST00000609795.5:c.740T>C

ENST00000619550.4:c.731T>C

NM_000457.4:c.806T>C

NM_001030003.2:c.740T>C

NM_001030004.2:c.740T>C

NM_001258355.1:c.785T>C

NM_001287182.1:c.731T>C

NM_001287183.1:c.731T>C

NM_001287184.1:c.731T>C

NM_175914.4:c.740T>C

NM_178849.2:c.806T>C

NM_178850.2:c.806T>C

NM_001030003.3:c.740T>C

NM_001030004.3:c.740T>C

NM_001258355.2:c.785T>C

NM_001287182.2:c.731T>C

NM_001287184.2:c.731T>C

NM_178849.3:c.806T>C

NM_178850.3:c.806T>C

NM_000457.5:c.806T>C

NM_000457.6:c.806T>C

NM_001287183.2:c.731T>C

Pathogenic

PP4_Moderate PP1_Moderate PS4 PM2_Supporting PP3

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 for HNF4A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.740T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 247 (p.(Leu247Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU ) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.733G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1_moderate, PP3, PP4_moderate, PM2_Supporting.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU ) (PP4_Moderate; internal lab contributors).

PP1_Moderate

This variant segregated with diabetes, with threee informative meioses in two families (PP1_Moderate; internal lab contributors).

PS4

This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.1.0, absent

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Curation History

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