ClinVar Miner

Submissions for variant NM_000143.3(FH):c.937G>A (p.Glu313Lys) (rs863224001)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199631 SCV000251472 likely pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing TThe E313K variant in the FH gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E313K 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (F312C, F312S, L315P, H318Y) have been reported in association with FH-related disorders, supporting the functional importance of this region of the protein (Coughlin et al., 1998; Toro et al., 2003; Gardie et al., 2011). Therefore, E313K is a strong candidate for a pathogenic variant. However the possibility that it is a rare benign variant cannot be excluded.
Invitae RCV000461129 SCV000544269 uncertain significance Fumarase deficiency 2016-09-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 313 of the FH protein (p.Glu313Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an FH-related disease. ClinVar contains an entry for this variant (Variation ID: 214414). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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