20-44413714-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got -3 ACMG points: 6P and 9B. PP3PP4BS2PP1_StrongBP5BS1
This summary comes from the ClinGen Evidence Repository: The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID:9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID:2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID:27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120206/MONDO:0015967/085
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
HNF4A
NM_175914.5 missense
NM_175914.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 2.50
Genes affected
HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got -3 ACMG points.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
BP5
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000658 AC: 10AN: 151998Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000797 AC: 20AN: 250910Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135642
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GnomAD4 exome AF: 0.000120 AC: 176AN: 1461616Hom.: 0 Cov.: 32 AF XY: 0.000118 AC XY: 86AN XY: 727104
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GnomAD4 genome 0.0000658 AC: 10AN: 151998Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74230
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:10Uncertain:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 16, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 114 of the HNF4A protein (p.Arg114Trp). This variant is present in population databases (rs137853336, gnomAD 0.01%). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 9313765, 11043869, 15830177, 25414397, 27486234, 29207974, 30977832; Invitae). It has also been observed to segregate with disease in related individuals. Of note, this variant has been observed to have reduced penetrance, with later average age of onset and decreased responsiveness to sulfonylurea treatment when compared to other HNF4A mutations (PMID: 27486234). This variant is also known as p.Arg127Trp or p.Arg136Trp. ClinVar contains an entry for this variant (Variation ID: 9212). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF4A function (PMID: 10389854, 10606640, 10819248, 16223942). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 03, 2024 | The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function, however the effect seen in these assays was less severe than for known pathogenic variants in this gene (PMID: 10606640, 10819248). This variant is also referred to as R127W and R114W in published literature. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2023 | 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, 34662886, 11272211, 10819248, 11043869, 17407387, 25414397, 24097065, 23551881, 27486234, 10606640, 29207974, 10389854, 30665703, 29998026, 29734081, 31281738, 9313765, 30191644, 30977832, 27271189, 26287533, 32041611, 24843605, 15752752, 23485969, 16223942) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Maturity onset diabetes mellitus in young Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 15, 2021 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2018 | 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. - |
Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Monogenic diabetes Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Dec 02, 2023 | The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID: 9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID: 2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID: 27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4. - |
Maturity-onset diabetes of the young type 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1997 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 07, 2021 | 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;D;.;D;D;.
Vest4
MVP
MPC
0.81
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at