ClinVar Miner

Submissions for variant NM_000143.3(FH):c.473G>A (p.Ser158Asn) (rs1060500902)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464397 SCV000544261 uncertain significance Fumarase deficiency 2016-05-09 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 158 of the FH protein (p.Ser158Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FH-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000498842 SCV000589405 likely pathogenic not provided 2015-04-30 criteria provided, single submitter clinical testing The S158N variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The S158N variant was not observed in approximately 6,500 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 S158N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in this residue (S158I) and in a nearby residue (R160G) has been reported in the Human Gene Mutation Database in association with FH-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, S158N is a strong candidate for a pathogenic variant, although the possibility that it is a benign polymorphism cannot be completely excluded.

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