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NM_175914.5(HNF4A):c.869G>A (p.Arg290His) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 6, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004527405.1

Allele description [Variation Report for NM_175914.5(HNF4A):c.869G>A (p.Arg290His)]

NM_175914.5(HNF4A):c.869G>A (p.Arg290His)

Gene:
HNF4A:hepatocyte nuclear factor 4 alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.12
Genomic location:
Preferred name:
NM_175914.5(HNF4A):c.869G>A (p.Arg290His)
Other names:
NM_175914.5(HNF4A):c.869G>A; p.Arg290His
HGVS:
  • NC_000020.11:g.44424060G>A
  • NG_009818.1:g.73260G>A
  • NM_000457.6:c.935G>A
  • NM_001030003.3:c.869G>A
  • NM_001030004.3:c.869G>A
  • NM_001258355.2:c.914G>A
  • NM_001287182.2:c.860G>A
  • NM_001287183.2:c.860G>A
  • NM_001287184.2:c.860G>A
  • NM_175914.5:c.869G>AMANE SELECT
  • NM_178849.3:c.935G>A
  • NM_178850.3:c.935G>A
  • NP_000448.3:p.Arg312His
  • NP_000448.3:p.Arg312His
  • NP_001025174.1:p.Arg290His
  • NP_001025175.1:p.Arg290His
  • NP_001245284.1:p.Arg305His
  • NP_001274111.1:p.Arg287His
  • NP_001274112.1:p.Arg287His
  • NP_001274113.1:p.Arg287His
  • NP_787110.2:p.Arg290His
  • NP_849180.1:p.Arg312His
  • NP_849181.1:p.Arg312His
  • LRG_483t1:c.869G>A
  • LRG_483t2:c.935G>A
  • LRG_483:g.73260G>A
  • LRG_483p2:p.Arg312His
  • NC_000020.10:g.43052700G>A
  • NC_000020.10:g.43052700G>A
  • NM_000457.4:c.935G>A
  • NM_175914.4:c.869G>A
  • NM_178850.2:c.935G>A
Protein change:
R287H
Links:
dbSNP: rs1191912908
NCBI 1000 Genomes Browser:
rs1191912908
Molecular consequence:
  • NM_000457.6:c.935G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030003.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001030004.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258355.2:c.914G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287182.2:c.860G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287183.2:c.860G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287184.2:c.860G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175914.5:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178849.3:c.935G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178850.3:c.935G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005040711ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF4A V2.0.0)		Pathogenic
(Apr 6, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV005040711.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.869G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 290 (p.(Arg290His)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Two of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sufonylurea-sensitive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 14 informative meioses in 6 families (PP1_Strong, internal lab contributors). In summary, c.869G>A 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, PP3, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 19, 2025