ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1000A>C (p.Ser334Arg) (rs587782216)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130899 SCV000185808 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Structural Evidence
Invitae RCV000525776 SCV000632431 likely pathogenic Fumarase deficiency 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 334 of the FH protein (p.Ser334Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with hereditary leiomyomatosis and renal cell cancer (HLRCC) in a family (Invitae). In addition, a different variant (c.1002T>G) giving rise to the same protein effect observed here (p.Ser334Arg) has been reported in families with HLRCC (PMID: 18514489, 22086304, 20618355), and was shown to segregate with disease in a family (PMID: 18514489, 22086304). ClinVar contains an entry for this variant (Variation ID: 142077). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.