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_175914.5(HNF4A):c.932G>A (p.Arg311His)

CA409108268

586023 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1ccfebcd-6207-4b34-85a4-4c4693ade736

Approved on: 2024-09-18

Published on: 2024-09-18

HGVS expressions

NM_175914.5:c.932G>A

NM_175914.5(HNF4A):c.932G>A (p.Arg311His)

NC_000020.11:g.44424123G>A

CM000682.2:g.44424123G>A

NC_000020.10:g.43052763G>A

CM000682.1:g.43052763G>A

NC_000020.9:g.42486177G>A

NG_009818.1:g.73323G>A

ENST00000316673.9:c.932G>A

ENST00000316099.10:c.998G>A

ENST00000619550.5:c.972G>A

ENST00000316099.9:c.998G>A

ENST00000316099.8:c.998G>A

ENST00000316673.8:c.932G>A

ENST00000372920.1:c.*765G>A

ENST00000415691.2:c.998G>A

ENST00000443598.6:c.998G>A

ENST00000457232.5:c.932G>A

ENST00000609795.5:c.932G>A

ENST00000619550.4:c.923G>A

NM_000457.4:c.998G>A

NM_001030003.2:c.932G>A

NM_001030004.2:c.932G>A

NM_001258355.1:c.977G>A

NM_001287182.1:c.923G>A

NM_001287183.1:c.923G>A

NM_001287184.1:c.923G>A

NM_175914.4:c.932G>A

NM_178849.2:c.998G>A

NM_178850.2:c.998G>A

NM_001030003.3:c.932G>A

NM_001030004.3:c.932G>A

NM_001258355.2:c.977G>A

NM_001287182.2:c.923G>A

NM_001287184.2:c.923G>A

NM_178849.3:c.998G>A

NM_178850.3:c.998G>A

NM_000457.5:c.998G>A

NM_000457.6:c.998G>A

NM_001287183.2:c.923G>A

Pathogenic

PP4_Moderate PP1_Strong PM1_Supporting PS4 PP3 PM2_Supporting PM5_Supporting

BP4 BA1 BS1

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.932G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 311 (p.(Arg311His)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to absence in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 25414397, 24947580 26059258, 32533152; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies; and family history of LGA/hypoglycemic infant) (PP4_Moderate; PMID: 24947580, internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 4 families (PP1_Strong; PMIDs: 24947580, 26059258, 32533152, internal lab contributors). Another missense variant, p.(Arg311Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg311His) (PM5_Supporting). In summary, c.932G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting, PS4, PP4_Moderate, PP1_Strong, PM5_Supporting.

PP4_Moderate

This variant was identified in at least two individuals with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies; and family history of LGA/hypoglycemic infant) (PP4_Moderate; PMID: 24947580, internal lab contributors).

PP1_Strong

This variant segregated with diabetes, with 12 informative meioses in 4 families (PP1_Strong; PMIDs: 24947580, 26059258, 32533152, internal lab contributors).

PM1_Supporting

This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PS4

This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 10768098, 24947580, 26059258, 29758564, 32533152, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to absence in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).

PM5_Supporting

Another missense variant at this amino acid, c.931C>T, p.(Arg311Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg311His (PM5_Supporting).

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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