ClinVar Miner

Submissions for variant NM_000143.3(FH):c.935T>G (p.Phe312Cys) (rs1553341046)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000635298 SCV000756695 likely pathogenic Fumarase deficiency 2018-01-12 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 312 of the FH protein (p.Phe312Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with fumarate hydratase deficiency (PMID: 9635293). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. 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.Phe312Leu) has been determined to be likely pathogenic (Invitae). This suggests that the phenylalanine residue is critical for FH protein function and that other missense substitutions at this position may also be likely pathogenic. 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.