NM_175914.5(HNF4A):c.869G>A (p.Arg290His) AND Maturity onset diabetes mellitus in young

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003317408.1

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:: Maturity onset diabetes mellitus in young (MODY)
Synonyms:: Mason type diabetes
Identifiers:: MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004020407	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16917892, 17407387, 18811724, 23348805, 30663027, 34440499 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004020407

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 21, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young.

Ellard S, Colclough K.

Hum Mutat. 2006 Sep;27(9):854-69.

PubMed [citation]

PMID:: 16917892

Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT.

PLoS Med. 2007 Apr;4(4):e118.

PubMed [citation]

PMID:: 17407387
PMCID:: PMC1845156

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020407.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: HNF4A c.869G>A (p.Arg290His) results in a non-conservative amino acid change located in the nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 (i.e., 1 heterozygote) in 248094 control chromosomes (gnomAD v2.1, Exomes dataset). c.869G>A has been reported in the literature in multiple families affected with Maturity Onset Diabetes Of The Young and hyperinsulinism (e.g., Ellard_2006, Pearson_2007, Plengvidhya_2008, Colclough_2013, Zubkova_2019, Gaal_2021), and the variant has been shown to segregate with disease in related individuals (e.g., Pearson_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23348805, 16917892, 34440499, 17407387, 18811724, 30663027). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as pathogenic (n = 2), likely pathogenic (n = 2), and VUS (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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