ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1256C>T (p.Ser419Leu) (rs1131691244)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000494270 SCV000581666 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,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,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000635292 SCV000756689 uncertain significance Fumarase deficiency 2017-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 419 of the FH protein (p.Ser419Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 429183). 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. A different missense substitution at this codon (p.Ser419Pro) has been determined to be pathogenic (PMID: 16597677, 15937070, Invitae). This suggests that the serine residue is critical for FH protein function and that other missense substitutions at this position may also be pathogenic. 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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