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 effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250910 control chromosomes. The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06), strongly suggesting that the variant is benign. c.340C>T has been widely reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus. In a cross sectional review of the literature supporting this variant, most reports provide contradictory or inconclusive evidence supporting a pathogenic outcome. In a Japanese family with this variant, 4 transmissions of the variant allele and 2 transmissions of the reference allele to affected individuals was reported. This family also contained two phenocopies diagnosed at age 11 and 36 as well as a heterozygote who was not diagnosed with diabetes until age 90 (Furuta_1997). Subsequently, this variant has been reported as a reduced penetrance variant with a distinct clinical phenotype that is different from that associated with HNF4A asssociated MODY (Laver_2016). It continues to be cited in the literature as a likely pathogenic variant citing questionable ascertainment criteria (Shi Park_2019). In contrast, another recent study evaluating the expressivity of putative disease causing variants in a population setting reports this variant as having a penetrance of less than 10% by the time an individual is 40 years old (Wright_2019). These data do not allow any conclusion about variant significance. At-least two co-occurrences with other pathogenic variant(s) have been reported ( HNF1A c.476G>A , p.R159Q; HNF1A c.872dup, p.Gly292fs), providing supporting evidence for a benign role (Laver_2016, Shankar_2013). Although one of these studies proposed a digenic role for this variant in the etiology of MODY (Shankar_2013). At least two publication reporting conflicting experimental evidence evaluating an impact on protein function were ascertained. One study reports 30%-50% of normal transactivation potential (Lausen_2000) while the other reports transactivation at levels identical to the wild-type control (Navas_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ClinVar Genomic variation as it relates to human health
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
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 NM_001030004.3:c.340C>T NP_001025175.1:p.Arg114Trp missense NM_001258355.2:c.385C>T NP_001245284.1:p.Arg129Trp missense NM_001287182.2:c.331C>T NP_001274111.1:p.Arg111Trp missense NM_001287183.2:c.331C>T NP_001274112.1:p.Arg111Trp missense NM_001287184.2:c.331C>T NP_001274113.1:p.Arg111Trp missense NM_178849.3:c.406C>T NP_849180.1:p.Arg136Trp missense NM_178850.3:c.406C>T NP_849181.1:p.Arg136Trp missense NC_000020.11:g.44413714C>T NC_000020.10:g.43042354C>T NG_009818.1:g.62914C>T LRG_483:g.62914C>T LRG_483t1:c.340C>T LRG_483p1:p.Arg114Trp LRG_483t2:c.406C>T LRG_483p2:p.Arg136Trp P41235:p.Arg136Trp - 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 |
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 |
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)
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 effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250910 control chromosomes. The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06), strongly suggesting that the variant is benign. c.340C>T has been widely reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus. In a cross sectional review of the literature supporting this variant, most reports provide contradictory or inconclusive evidence supporting a pathogenic outcome. In a Japanese family with this variant, 4 transmissions of the variant allele and 2 transmissions of the reference allele to affected individuals was reported. This family also contained two phenocopies diagnosed at age 11 and 36 as well as a heterozygote who was not diagnosed with diabetes until age 90 (Furuta_1997). Subsequently, this variant has been reported as a reduced penetrance variant with a distinct clinical phenotype that is different from that associated with HNF4A asssociated MODY (Laver_2016). It continues to be cited in the literature as a likely pathogenic variant citing questionable ascertainment criteria (Shi Park_2019). In contrast, another recent study evaluating the expressivity of putative disease causing variants in a population setting reports this variant as having a penetrance of less than 10% by the time an individual is 40 years old (Wright_2019). These data do not allow any conclusion about variant significance. At-least two co-occurrences with other pathogenic variant(s) have been reported ( HNF1A c.476G>A , p.R159Q; HNF1A c.872dup, p.Gly292fs), providing supporting evidence for a benign role (Laver_2016, Shankar_2013). Although one of these studies proposed a digenic role for this variant in the etiology of MODY (Shankar_2013). At least two publication reporting conflicting experimental evidence evaluating an impact on protein function were ascertained. One study reports 30%-50% of normal transactivation potential (Lausen_2000) while the other reports transactivation at levels identical to the wild-type control (Navas_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
|
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 |
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)
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 has been reported to be enriched in MODY patients with reduced penetrance in families (PMID: 27486234). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. This variant is also referred to as R127W in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant showed decreased transactivation potential and decreased DNA binding ability (PMID: 10606640, 10819248). Computational tools predict that this variant is damaging. (less)
|
|
|
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)
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 some pedigrees (Furuta et al., 1997; Shankar et al., 2013; Flannick et al., 2013; Delvecchio et al., 2014; Laver et al., 2016); Published functional studies show wild-type target gene activation is retained, however, abnormal transcriptional activation and altered activity during indirect target gene regulation occurs (Rowley et al., 2006); 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: 15830177, 29377200, 11272211, 10819248, 11043869, 17407387, 25414397, 24097065, 23551881, 27486234, 10606640, 29207974, 10389854, 16223942, 30665703, 29998026, 29734081, 31281738, 9313765, 30191644, 30977832, 27271189, 26287533, 32041611) (less)
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|
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 |
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)
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 substitution at nucleotide position 340. The arginine at codon 114 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was first reported in a Japanese maturity onset diabetes of the young (MODY) family (Furuta H et al. Diabetes, 1997 Oct;46:1652-7) and was subsequently reported in two Italian individuals with MODY (Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60). This mutation has shown strong segregation with disease across multiple pedigrees; however, when compared to other mutations in HNF4A, reduced penetrance (54% vs. 71% by age 30), later age of onset (median 34 vs. 24, p=0.018), and decreased responsiveness to sulfonylurea treatment (48% vs. 73%, p = 0.038) were observed (Laver TW et al. Diabetes, 2016 Oct;65:3212-7). Although transactivation activity of this mutation was observed to be normal in one study (Navas MA et al. Diabetes, 1999 Jul;48:1459-65), additional studies using multiple conditions and additional cell lines have shown that DNA binding and transactivation ability is reduced by approximately 50% due to this mutation (Lausen J et al. Nucleic Acids Res., 2000 Jan;28:430-7; Yang Q et al. Diabetologia, 2000 Apr;43:520-4). Based on structural analysis, this alteration will disrupt proper dimerization of the receptor and DNA binding (Chandra V et al. Nature, 2013 Mar;495:394-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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 |
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)
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 CGG to TGG. The mutation was located in the T-box, a region of the protein that may play a role in HNF-4-alpha dimerization and DNA binding. The findings in the family suggested that the R172W mutation was not the only cause of diabetes. The overall results suggested that mutations in the HNF4A gene may cause early onset NIDDM/MODY in Japanese but such mutations are less common than mutations in the HNF1A/MODY3 gene (142410). (less)
|
|
|
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...
HelpThese 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