ClinVar Miner

Submissions for variant NM_000143.3(FH):c.934T>C (p.Phe312Leu) (rs863224000)

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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 RCV000493445 SCV000581679 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000197788 SCV000251471 likely pathogenic not provided 2016-10-18 criteria provided, single submitter clinical testing The F312L variant that is likely pathogenic was identified in the FH gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The F312L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F312L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is highly conserved across vertebrate species and in silico analyses predict this variant is probably damaging to the protein structure/function. Additionally, a missense variant in this same residue, F312S, has been reported in association with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Gardie et al., 2011). Missense variants in nearby residues (L303S, A308T, N310Y, L315P, A317V, H318Y) have been reported with FH-related disease, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for being pathogenic, however the possibility that it is a benign variant cannot be excluded. The variant is found in FH panel(s).
Invitae RCV000533544 SCV000632497 likely pathogenic Fumarase deficiency 2017-11-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 312 of the FH protein (p.Phe312Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family in which several members have a clinical history that is suspicious for hereditary leiomyomatosis and renal cell cancer (HLRCC) (Invitae). ClinVar contains an entry for this variant (Variation ID: 214413). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Phe312Ser, also known as Phe269Ser) has been reported in an individual with suspected hereditary leiomyomatosis and renal cell cancer (PMID: 21398687). Another missense substitution at this codon (p.Phe312Cys, also known as Phe269Cys) has been reported in trans with a likely pathogenic FH allele in an individual with fumarate hydratase deficiency (PMID: 9635293). This suggests that the phenylalanine residue is critical for FH protein function and that other missense substitutions at this position may also be 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.

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