NM_175914.5(HNF4A):c.869G>A (p.Arg290His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000992167.12

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)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001144214	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	pathogenic (Sep 13, 2024)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 36257325, 34440499, 17407387, 18811724, 27552834, 30663027, 25555642, 26467025
SCV002067525	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 18, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003443812	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 10, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30447144, 17407387, 26971647, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001144214

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

pathogenic
(Sep 13, 2024)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002067525

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 18, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003443812

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 10, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM; Geisinger-Regeneron DiscovEHR Collaboration, Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA.

Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. doi: 10.1016/j.ajhg.2022.09.014. Epub 2022 Oct 17.

PubMed [citation]

PMID:: 36257325
PMCID:: PMC9674944

A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes.

Gaál Z, Szűcs Z, Kántor I, Luczay A, Tóth-Heyn P, Benn O, Felszeghy E, Karádi Z, Madar L, Balogh I.

Life (Basel). 2021 Jul 27;11(8). doi: 10.3390/life11080755.

PubMed [citation]

PMID:: 34440499
PMCID:: PMC8399091

See all PubMed Citations (12)

Details of each submission

From Athena Diagnostics, SCV001144214.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In some published literature, this variant is referred to as c.869G>A (p.Arg290His) or c.908G>A (p.Arg303His). Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease.

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

From Genetic Services Laboratory, University of Chicago, SCV002067525.1

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

Description

DNA sequence analysis of the HNF4A gene demonstrated a sequence change, c.869G>A, in exon 8 that results in an amino acid change, p.Arg290His. This sequence change has been identified in a patient with gestational diabetes mellitus (GDM) (PMID: 30663027). A different sequence change affecting the same amino acid residue (p.Arg290Cys) has been described in an individual with diabetes at the age of 28 years and several of his family members who were either diagnosed with early onset diabetes or impaired glucose tolerance. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs1191912908). The p.Arg290His change affects a highly conserved amino acid residue located in a dimerization domain of the HNF4A protein that is known to be functional. The p.Arg290His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443812.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg290 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been observed in individuals with HNF4A-related conditions (PMID: 30447144), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 804918). This missense change has been observed in individuals with autosomal dominant familial hyperinsulinism and/or autosomal dominant maturity-onset diabetes of the young (PMID: 17407387, 26971647; Invitae). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 290 of the HNF4A protein (p.Arg290His).

#	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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