ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1048C>T (p.Arg350Trp) (rs755436052)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198662 SCV000251477 likely pathogenic not provided 2014-06-12 criteria provided, single submitter clinical testing p.Arg350Trp (CGG>TGG): c.1048 C>T in exon 7 in the FH gene (NM_000143.3). The R350W variant in the FH gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R350W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R350W 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. Missense mutations in nearby residues have been reported in association with hereditary leiomyomatosis and/or renal cell cancer (N340K, D341Y, D341N, E355K) as well as fumarate hydratase deficiency (G346D), supporting the functional importance of this region of the protein. The R350W variant is a good candidate for a disease-causing mutation, however the possibility it may be a rare benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Invitae RCV000696839 SCV000825418 uncertain significance Fumarase deficiency 2018-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 350 of the FH protein (p.Arg350Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs755436052, ExAC 0.006%). This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 214418). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000696839 SCV000891505 uncertain significance Fumarase deficiency 2017-12-30 criteria provided, single submitter curation

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