Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

ClinVar Genomic variation as it relates to human health

Advanced search

NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)

Help
Interpretation:
Conflicting interpretations of pathogenicity​

Pathogenic(3); Likely pathogenic(1); Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
10
First in ClinVar:
Aug 22, 2016
Most recent Submission:
Nov 29, 2022
Last evaluated:
May 10, 2022
Accession:
VCV000009212.18
Variation ID:
9212
Description:
single nucleotide variant
Help

NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)

Allele ID
24251
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
20q13.12
Genomic location
20: 44413714 (GRCh38) GRCh38 UCSC
20: 43042354 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_175914.5:c.340C>T MANE Select NP_787110.2:p.Arg114Trp missense
NM_000457.6:c.406C>T NP_000448.3:p.Arg136Trp missense
NM_001030003.3:c.340C>T NP_001025174.1:p.Arg114Trp missense
... more HGVS
Protein change
R114W, R129W, R136W, R111W
Other names
R127W
Canonical SPDI
NC_000020.11:44413713:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Links
ClinGen: CA120206
UniProtKB: P41235#VAR_004668
OMIM: 600281.0003
dbSNP: rs137853336
VarSome
Help

Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Apr 7, 2021 RCV001375546.2
Pathogenic 1 criteria provided, single submitter Jun 30, 2021 RCV001536085.3
Pathogenic 1 criteria provided, single submitter Jun 20, 2018 RCV002453254.1
Conflicting interpretations of pathogenicity 6 criteria provided, conflicting interpretations May 10, 2022 RCV000711955.14
Pathogenic 1 no assertion criteria provided Oct 1, 1997 RCV000009792.7
Help
Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
HNF4A - - GRCh38
GRCh37
423 448

Submitted interpretations and evidence

Help
Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter More information
Uncertain significance
(Apr 07, 2021)
criteria provided, single submitter
Method: clinical testing
not specified
Affected status: unknown
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572413.1
First in ClinVar: Apr 30, 2021
Last updated: Apr 30, 2021
Publications:
PubMed (13)
Comment:
Variant summary: HNF4A c.340C>T (p.Arg114Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Pathogenic
(May 28, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: unknown
Athena Diagnostics Inc
Accession: SCV000842366.3
First in ClinVar: Oct 20, 2018
Last updated: Sep 19, 2021
Publications:
PubMed (13)
Comment:
This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls which is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant … (more)
Likely pathogenic
(Feb 16, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
Genetic Services Laboratory,University of Chicago
Accession: SCV002070506.1
First in ClinVar: Jan 29, 2022
Last updated: Jan 29, 2022
Uncertain significance
(Jul 13, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
Invitae
Accession: SCV002141894.1
First in ClinVar: Mar 28, 2022
Last updated: Mar 28, 2022
Uncertain significance
(May 10, 2022)
criteria provided, single submitter
Method: clinical testing
Not Provided
Affected status: yes
Allele origin: germline
GeneDx
Accession: SCV000617566.3
First in ClinVar: Dec 19, 2017
Last updated: May 28, 2022
Comment:
Identified in individuals with diabetes; however, variant has also been reported in individuals and family members without diabetes, and does not cosegregate with disease in … (more)
Pathogenic
(Jun 20, 2018)
criteria provided, single submitter
Method: clinical testing
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin: germline
Ambry Genetics
Accession: SCV002612745.1
First in ClinVar: Nov 29, 2022
Last updated: Nov 29, 2022
Publications:
PubMed (9)
Comment:
The p.R114W pathogenic mutation (also known as c.340C>T and R127W), located in coding exon 4 of the HNF4A gene, results from a C to T … (more)
Number of individuals with the variant: 1
Pathogenic
(Jun 30, 2021)
criteria provided, single submitter
Method: clinical testing
Maturity-onset diabetes of the young type 1
Type 2 diabetes mellitus
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
Affected status: unknown
Allele origin: unknown
Fulgent Genetics, Fulgent Genetics
Accession: SCV001752788.1
First in ClinVar: Jul 18, 2021
Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
Pathogenic
(Oct 01, 1997)
no assertion criteria provided
Method: literature only
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1
Affected status: not provided
Allele origin: germline
OMIM
Accession: SCV000030013.2
First in ClinVar: Apr 04, 2013
Last updated: Aug 22, 2016
Publications:
PubMed (1)
PubMed: 9313765
Comment on evidence:
In 3 of 5 members with MODY (125850) in 1 family, Furuta et al. (1997) identified an arg127-to-trp (R127W) mutation resulting from a transition from … (more)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035289.1
First in ClinVar: Dec 18, 2021
Last updated: Dec 18, 2021
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035521.1
First in ClinVar: Dec 18, 2021
Last updated: Dec 18, 2021

Functional evidence

Help
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

Help
Title Author Journal Year Link
Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population. Park SS The Journal of clinical endocrinology and metabolism 2019 PMID: 30977832
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. Wright CF American journal of human genetics 2019 PMID: 30665703
Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. Johnson SR Pediatric diabetes 2019 PMID: 30191644
Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. Bansal V BMC medicine 2017 PMID: 29207974
The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes. Laver TW Diabetes 2016 PMID: 27486234
Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Flannick J Nature reviews. Endocrinology 2016 PMID: 27080136
Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. Delvecchio M Diabetes care 2014 PMID: 25414397
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Flannick J Nature genetics 2013 PMID: 24097065
Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes. Shankar RK Pediatric diabetes 2013 PMID: 23551881
Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Chandra V Nature 2013 PMID: 23485969
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. Pearson ER PLoS medicine 2007 PMID: 17407387
Mechanisms of mutual functional interactions between HNF-4alpha and HNF-1alpha revealed by mutations that cause maturity onset diabetes of the young. Rowley CW American journal of physiology. Gastrointestinal and liver physiology 2006 PMID: 16223942
Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Pearson ER Diabetologia 2005 PMID: 15830177
beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Frayling TM Diabetes 2001 PMID: 11272211
R127W in HNF4alpha is a loss-of-function mutation causing maturity-onset diabetes of the young (MODY) in a UK Caucasian family. Bulman MP Diabetologia 2000 PMID: 11043869
R127W-HNF-4alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1. Yang Q Diabetologia 2000 PMID: 10819248
Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree. Lausen J Nucleic acids research 2000 PMID: 10606640
Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). Navas MA Diabetes 1999 PMID: 10389854
Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Furuta H Diabetes 1997 PMID: 9313765

Text-mined citations for rs137853336...

Help
These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 11, 2022