Submissions for variant NM_000143.4(FH):c.908T>C (p.Leu303Ser)

gnomAD frequency: 0.00001  dbSNP: rs201502246

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034486	SCV000544239	likely pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 303 of the FH protein (p.Leu303Ser). This variant is present in population databases (rs201502246, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive fumarase deficiency and/or paraganglioma-pheochromocytoma syndrome (PMID: 22595425, 35821608; Invitae). ClinVar contains an entry for this variant (Variation ID: 41584). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 22595425). 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	RCV000568576	SCV000673377	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The p.L303S variant (also known as c.908T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 908. The leucine at codon 303 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified, in trans with another FH missense alteration, in a 12-year-old girl with mild fumarase deficiency (Kimonis VE et al. Mol. Genet. Metab. 2012 Sep;107:241-2). This variant has also been reported in an individual with an adrenal pheochromocytoma whose tumor demonstrated loss of heterozygosity of FH; this individual's father also had a history of renal cell carcinoma (Richter S et al. Genet. Med. 2018 Jul). Based on internal structural analysis, L303S is more disruptive to the central domain than several nearby internally pathogenic variants (Ambry internal data; Ajalla Aleixo MA et al. FEBS J 2019 05;286(10):1925-1940). This amino acid position is highly 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 expected to be causative of autosomal recessive FH deficiency when present along with a second likely pathogenic/pathogenic variant on the other allele; however, the clinical significance for autosomal dominant HLRCC is unclear.
GeneDx	RCV000034486	SCV001986003	uncertain significance	not provided	2024-03-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of pheochromocytoma whose tumor demonstrated loss of FH on immunohistochemistry testing and who also had a family history of renal cancer (PMID: 30050099); This variant is associated with the following publications: (PMID: 22595425, 22703879, 20549362, 30761759, 33052056, 35821608, 35993574, 36773955, 30050099)
Sema4, Sema4	RCV000568576	SCV002535579	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000034486	SCV004224834	uncertain significance	not provided	2022-11-09	criteria provided, single submitter	clinical testing	PP3, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767031	SCV005381789	uncertain significance	not specified	2024-08-26	criteria provided, single submitter	clinical testing	Variant summary: FH c.908T>C (p.Leu303Ser) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.908T>C has been reported in the literature in a compound heterozygous individual affected with fumarase deficiency (e.g. Kimonis_2012) and an individual affected with a pheochromocytoma with a father affected with renal cell carcinoma (e.g. Richter_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect on catalytic activity of this variant in vitro (e.g. Wilde_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22595425, 30050099, 37255402). ClinVar contains an entry for this variant (Variation ID: 41584). Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034486	SCV000043260	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Natera, Inc.	RCV000471678	SCV002085844	uncertain significance	Fumarase deficiency	2021-08-10	no assertion criteria provided	clinical testing