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

gnomAD frequency: 0.00006  dbSNP: rs137853336

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003445066	SCV004174222	likely pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	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.
GeneDx	RCV000711955	SCV000617566	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	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)
Athena Diagnostics	RCV000711955	SCV000842366	pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375546	SCV001572413	uncertain significance	not specified	2021-04-07	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV001536085	SCV001752788	pathogenic	Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2021-06-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000711955	SCV002070506	likely pathogenic	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711955	SCV002141894	likely pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002453254	SCV002612745	pathogenic	Maturity onset diabetes mellitus in young	2018-06-20	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002453254	SCV004848510	pathogenic	Maturity onset diabetes mellitus in young	2021-03-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
OMIM	RCV000009792	SCV000030013	pathogenic	Maturity-onset diabetes of the young type 1	1997-10-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000711955	SCV002035289	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000711955	SCV002035521	pathogenic	not provided		no assertion criteria provided	clinical testing