NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 19, 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:: RCV000489797.18

Allele description [Variation Report for NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)]

NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)

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.335G>A (p.Arg112Gln)

Other names:

NM_175914.5(HNF4A):c.335G>A; p.Arg112Gln

HGVS:

NC_000020.11:g.44413709G>A
NG_009818.1:g.62909G>A
NM_000457.6:c.401G>A
NM_001030003.3:c.335G>A
NM_001030004.3:c.335G>A
NM_001258355.2:c.380G>A
NM_001287182.2:c.326G>A
NM_001287183.2:c.326G>A
NM_001287184.2:c.326G>A
NM_175914.5:c.335G>AMANE SELECT
NM_178849.3:c.401G>A
NM_178850.3:c.401G>A
NP_000448.3:p.Arg134Gln
NP_000448.3:p.Arg134Gln
NP_001025174.1:p.Arg112Gln
NP_001025175.1:p.Arg112Gln
NP_001245284.1:p.Arg127Gln
NP_001274111.1:p.Arg109Gln
NP_001274112.1:p.Arg109Gln
NP_001274113.1:p.Arg109Gln
NP_787110.2:p.Arg112Gln
NP_849180.1:p.Arg134Gln
NP_849181.1:p.Arg134Gln
LRG_483t1:c.335G>A
LRG_483t2:c.401G>A
LRG_483:g.62909G>A
LRG_483p2:p.Arg134Gln
NC_000020.10:g.43042349G>A
NM_000457.4:c.401G>A
NM_175914.3:c.335G>A
NM_175914.4:c.335G>A

Protein change:

R109Q

Links:

dbSNP: rs1085307913

NCBI 1000 Genomes Browser:

rs1085307913

Molecular consequence:

NM_000457.6:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001030003.3:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001030004.3:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258355.2:c.380G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287182.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287183.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001287184.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_175914.5:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178849.3:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178850.3:c.401G>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
SCV000577655	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 19, 2024)	germline	clinical testing	Citation Link,
SCV001476475	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	pathogenic (Dec 28, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18356407, 36257325, 35737141, 31825128, 36208030, 23348805, 26552609, 25306193, 24285859, 26467025
SCV002245462	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18356407, 26552609, 31825128, 28492532
SCV003839588	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Likely pathogenic (Aug 8, 2022)	germline	clinical testing

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

Search for a time- and cost-saving genetic testing strategy for maturity-onset diabetes of the young.

Dusatkova P, Pavlikova M, Elblova L, Larionov V, Vesela K, Kolarova K, Sumnik Z, Lebl J, Pruhova S.

Acta Diabetol. 2022 Sep;59(9):1169-1178. doi: 10.1007/s00592-022-01915-x. Epub 2022 Jun 23.

PubMed [citation]

PMID:: 35737141
PMCID:: PMC9219402

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000577655.7

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23348805, 31825128, 36257325, 33149276, 26552609, 25306193, 34789499, 18356407, 36208030, 18829458, 38733153)

#	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 Athena Diagnostics, SCV001476475.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) In some published literature, this variant is referred to as c.335G>A (p.Arg112Gln) or c.374G>A (p.Arg125Gln).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002245462.3

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the HNF4A protein (p.Arg112Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 18356407, 26552609, 31825128; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 427034). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. For these reasons, this variant has been 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

From Genetic Services Laboratory, University of Chicago, SCV003839588.1

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

Description

DNA sequence analysis of the HNF4A gene demonstrated a sequence change, c.335G>A, in exon 4 that results in an amino acid change, p.Arg112Gln. The p.Arg112Gln change affects a highly conserved amino acid residue located in a domain of the HNF4A protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg112Gln substitution. This sequence change has been described in individuals with MODY and renal cysts (PMID: 26552609, 18356407, 31825128). This sequence change has not been described in population databases such as ExAC and gnomAD. This sequence change is the likely cause of this individual's phenotype, 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

Last Updated: Jan 26, 2025

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