ClinVar Miner

Submissions for variant NM_000143.3(FH):c.560C>T (p.Ser187Leu) (rs398123166)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492920 SCV000581644 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445604 SCV000537237 uncertain significance Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV000800258 SCV000939959 uncertain significance Fumarase deficiency 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 187 of the FH protein (p.Ser187Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs398123166, ExAC 0.002%). This variant has been observed in an individual affected with hereditary leiomyomatosis and renal cell cancer (HLRCC)(PMID: 12772087). This variant is also known as C431T and S144L in the literature. ClinVar contains an entry for this variant (Variation ID: 393567). 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.

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