ClinVar Miner

Submissions for variant NM_175914.4(HNF4A):c.340C>T (p.Arg114Trp) (rs137853336)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000711955 SCV000617566 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing The R114W variant in the HNF4A gene has been reported previously, using alternate nomenclature R127W, in individuals with diabetes, however it has also been reported in individuals and family members without diabetes, and does not cosegregate in some pedigrees (Furuta et al., 1997; Shankar et al., 2013; Flannick et al., 2013; Delvecchio et al., 2014; Laver et al., 2016). The R114W variant is observed in 7/64396 (0.011%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R114W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R114W as a variant of uncertain significance.
Athena Diagnostics Inc RCV000711955 SCV000842366 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing This variant has been reported to be enriched in MODY patients with reduced penetrance in families. The frequency of this variant in the general population is consistent with pathogenicity. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant associates with disease in multiple families.
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.
OMIM RCV000009792 SCV000030013 pathogenic Maturity-onset diabetes of the young, type 1 1997-10-01 no assertion criteria provided literature only

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