Submissions for variant NM_000143.4(FH):c.998G>A (p.Cys333Tyr)

dbSNP: rs1553341032

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001784211	SCV000756713	likely pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function. ClinVar contains an entry for this variant (Variation ID: 529826). This variant is also known as c.869G>A, p.Cys290Tyr. This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 17768033, 21398687; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 333 of the FH protein (p.Cys333Tyr). Experimental studies have shown that this missense change affects FH function (PMID: 21398687). 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.
Ambry Genetics	RCV002386009	SCV002689652	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.C333Y variant (also known as c.998G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 998. The cysteine at codon 333 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant (also designated as C290Y) has been identified in multiple individuals with HLRCC (Makino T et al. J Dermatol Sci, 2007 Nov;48:151-3; Gardie B et al. J Med Genet, 2011 Apr;48:226-34; Muller M et al. Clin Genet, 2017 Dec;92:606-615). This alteration was also found to reduce FH activity to 40% compared to wildtype (Gardie B et al. J Med Genet, 2011 Apr;48:226-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV001784211	SCV004036333	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.869G>A p.(C290Y); This variant is associated with the following publications: (PMID: 21445611, 21398687, 12761039, 28300276, 17768033)