Submissions for variant NM_000143.4(FH):c.1097G>A (p.Ser366Asn)

dbSNP: rs863224004

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200592	SCV000251478	pathogenic	not provided	2024-02-20	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 FH c.968G>A, p.Ser323Asn; This variant is associated with the following publications: (PMID: 15937070, 12761039, 31299266, 18366737, 21630274, 12772087, 16597677, 16029320, 16237213, 30761759, 22561013, 35022142, 31831373, 21445611)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200592	SCV000283661	pathogenic	not provided	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 366 of the FH protein (p.Ser366Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple cutaneous and uterine leiomyomatosis (MCUL) or hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039, 12772087, 16237213; Invitae). This variant is also known as G968A or S323N. ClinVar contains an entry for this variant (Variation ID: 214419). 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%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001017278	SCV001178332	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The p.S366N pathogenic mutation (also known as c.1097G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 1097. The serine at codon 366 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with multiple cutaneous and uterine leiyomyomatosis (Alam NA et al. J Mol Diagn. 2005 Oct;7:437-43; Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73:95-106; Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11; Gupta S et al. Hum Pathol, 2019 Sep;91:114-122; Ambry internal data). Immunohistochemical analysis of tumors in patients with the germline p.S366N mutation have shown that this alteration results in an accumulation of succinated proteins as a result of deficient fumarase; these patients' tumors also demonstrated loss of heterozygosity (Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11). In addition, the p.S366N variant has been predicted to alter the enzymatic active site of the FH protein (Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ajalla Aleixo MA et al. FEBS J. 2019 May;286:1925-1940; Mechaly AE et al. FEBS Lett. 2012 Jun;586:1606-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as S323N (c.968G>A) in some published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291591	SCV002584686	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2022-10-03	criteria provided, single submitter	clinical testing	The FH c.1097G>A (p.Ser366Asn) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been identified in multiple individuals with leiomyomas and/or renal cell carcinoma (PMID: 12761039, 12772087, 21630274). The tumors of at least three of these individuals also demonstrated loss of heterozygosity (PMID: 12761039, 21630274). In addition, immunohistochemical analysis of tumors from patients with this germline variant have shown an accumulation of succinated proteins as a result of fumarase deficiency (PMID: 21630274). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is also known as p.Ser323Asn in the literature. In summary, this variant meets criteria to be classified as likely pathogenic.
Myriad Genetics, Inc.	RCV002291591	SCV003806649	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-01-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12761039, 31299266, 31831373, 21630274, 12772087].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000200592	SCV004218860	pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	The FH c.1097G>A (p.Ser366Asn) variant has been reported in the published literature in individuals with phenotypes associated with hereditary leiomyomatosis and renal cell cancer (HLRCC)(PMID: 12772087 (2003), 16237213 (2005), 21630274 (2011), 31299266 (2019)). Immunohistochemical analysis of tumors from patients with this variant showed loss of heterozygosity and were positive for (2-succinyl) cysteine (2SC) (termed protein succination) due to deficient fumarase (PMID: 21630274 (2011)). Additionally, this variant is predicted to alter the active site of the FH protein (PMID: 21445611 (2011), 12761039 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV004567402	SCV005057774	likely pathogenic	Fumarase deficiency	2023-12-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000200592	SCV005414261	likely pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	PP3, PP4, PP5, PM1, PM2_moderate