ClinVar Miner

Submissions for variant NM_000143.3(FH):c.952C>T (p.His318Tyr) (rs398123168)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445608 SCV000537249 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078152 SCV000109990 pathogenic not provided 2013-10-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762893 SCV000893293 likely pathogenic Fumarase deficiency; Multiple cutaneous leiomyomas 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000078152 SCV000251474 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted FH c.952C>T at the cDNA level, p.His318Tyr (H318Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant, also described as FH His275Tyr using alternate nomenclature, has been reported in multiple individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) and co-segregated with disease in several families (Martinez-Mir 2003, Toro 2003, Alam 2005, Smit 2011, Aissani 2015, Sommer 2016, Muller 2017). In vitro assays have demonstrated that FH His275Tyr is associated with significantly reduced fumarase activity (Pithukpakorn 2006, Bulku 2018). FH His318Tyr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000635300 SCV000756697 pathogenic Fumarase deficiency 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 318 of the FH protein (p.His318Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in multiple families with hereditary leiomyomatosis and renal cell cancer (HLRCC) or multiple cutaneous and uterine leiomyoma (MCUL) (PMID: 12772087, 14632190, 20618355). In the literature, this variant is also known as 823C>T or H275Y. ClinVar contains an entry for this variant (Variation ID: 92458). An analysis of the FH protein crystal structure revealed that the His318 residue is semi-conserved and localized in core helices. Variants affecting this residue (p.His318Tyr and p.His318Leu) are predicted to affect functional interactions with other proteins (PMID: 21445611). For these reasons, this variant has been classified as Pathogenic.

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