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.200G>A (p.Arg67Gln)

Curation Version - 1.1
Curation History
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CA409103974

435436 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 52fc616a-f4a7-4bab-8217-946ff8373ccc

Approved on: 2024-04-06

Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.200G>A

NM_175914.5(HNF4A):c.200G>A (p.Arg67Gln)

NC_000020.11:g.44406208G>A

CM000682.2:g.44406208G>A

NC_000020.10:g.43034848G>A

CM000682.1:g.43034848G>A

NC_000020.9:g.42468262G>A

NG_009818.1:g.55408G>A

ENST00000316673.9:c.200G>A

ENST00000316099.10:c.266G>A

ENST00000619550.5:c.240G>A

ENST00000681977.1:c.242G>A

ENST00000682169.1:c.219G>A

ENST00000683148.1:n.242G>A

ENST00000683657.1:n.242G>A

ENST00000684046.1:c.242G>A

ENST00000684136.1:c.242G>A

ENST00000684476.1:c.223G>A

ENST00000316099.9:c.266G>A

ENST00000316099.8:c.266G>A

ENST00000316673.8:c.200G>A

ENST00000372920.1:c.*33G>A

ENST00000415691.2:c.266G>A

ENST00000443598.6:c.266G>A

ENST00000457232.5:c.200G>A

ENST00000609262.5:c.191G>A

ENST00000609795.5:c.200G>A

ENST00000619550.4:c.191G>A

NM_000457.4:c.266G>A

NM_001030003.2:c.200G>A

NM_001030004.2:c.200G>A

NM_001258355.1:c.245G>A

NM_001287182.1:c.191G>A

NM_001287183.1:c.191G>A

NM_001287184.1:c.191G>A

NM_175914.4:c.200G>A

NM_178849.2:c.266G>A

NM_178850.2:c.266G>A

NM_001030003.3:c.200G>A

NM_001030004.3:c.200G>A

NM_001258355.2:c.245G>A

NM_001287182.2:c.191G>A

NM_001287184.2:c.191G>A

NM_178849.3:c.266G>A

NM_178850.3:c.266G>A

NM_000457.5:c.266G>A

NM_000457.6:c.266G>A

NM_001287183.2:c.191G>A

Pathogenic

PP1_Strong PS4 PP3 PM5_Supporting PM2_Supporting PP4_Moderate

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.200G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 67 (p.(Arg67Gln)) of NM_175914.5. This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting). This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors). At least 3 of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln) (PM5_Supporting). In summary, the c.200G>A variant 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): PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting.

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor).

PS4

This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM5_Supporting

Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln) (PM5_Supporting).

PM2_Supporting

This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting).

PP4_Moderate

This variant was identified in at least 3 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors).

Curation History

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