ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1255T>C (p.Ser419Pro) (rs200004220)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492881 SCV000581641 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445624 SCV000537264 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078144 SCV000109982 likely pathogenic not provided 2012-12-20 criteria provided, single submitter clinical testing
Invitae RCV000461249 SCV000544243 pathogenic Fumarase deficiency 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 419 of the FH protein (p.Ser419Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple families with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 15937070, Invitae). In the published family, this variant segregated with disease and was identified in all three affected family members while absent in the four tested, unaffected relatives. This variant is also known as c.1126T>C (p.Ser376Pro) in the literature. ClinVar contains an entry for this variant (Variation ID: 92451). 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. In an experimental study using fibroblast cells derived from a patient with HLRCC, it was shown that cells carrying the p.Ser419Pro missense change exhibited fumarate hydratase (FH) enzyme activity levels similar to patient cells carrying known pathogenic FH variants (PMID: 16597677). For these reasons, this variant has been classified as Pathogenic.

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