ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs137853336
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000711955 SCV000617566 uncertain significance not provided 2022-05-10 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, 11272211, 10819248, 11043869, 17407387, 25414397, 24097065, 23551881, 27486234, 10606640, 29207974, 10389854, 16223942, 30665703, 29998026, 29734081, 31281738, 9313765, 30191644, 30977832, 27271189, 26287533, 32041611)
Athena Diagnostics Inc 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
Invitae RCV000711955 SCV002141894 uncertain significance not provided 2021-07-13 criteria provided, single submitter clinical testing
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

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