Submissions for variant NM_000143.4(FH):c.217G>A (p.Val73Met)

gnomAD frequency: 0.00010  dbSNP: rs201878591

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163293	SCV000213821	likely benign	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001532106	SCV000544250	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 73 of the FH protein (p.Val73Met). This variant is present in population databases (rs201878591, gnomAD 0.01%). This missense change has been observed in individual(s) with paraganglioma (PMID: 30877234). ClinVar contains an entry for this variant (Variation ID: 184137). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FH protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001532106	SCV001753169	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Observed in individuals with renal cell carcinoma or head/neck paraganglioma (PMID: 30877234, 37095444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29641532, 26927868, 30877234, 37095444)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291575	SCV002584612	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2023-11-28	criteria provided, single submitter	clinical testing	The FH c.217G>A (p.Val73Met) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000467508	SCV004197302	uncertain significance	Fumarase deficiency	2024-02-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001532106	SCV004218875	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	The FH c.217G>A (p.Val73Met) variant has been reported in the published literature in individuals affected with early onset renal cell carcinoma (PMID: 37095444 (2023)), head and neck paraganglioma (PMID: 30877234 (2019)), and in a uterine leiomyoma (PMID: 32612247 (2020)). It was also identified in a child showing global developmental delay (PMID: 38539105 (2024)) and in an individual reportedly not affected with cancer (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.00012 (16/129174 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596082	SCV005090912	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016486	SCV005644201	uncertain significance	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2024-03-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000467508	SCV002085892	uncertain significance	Fumarase deficiency	2020-01-31	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004555540	SCV004113192	uncertain significance	FH-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The FH c.217G>A variant is predicted to result in the amino acid substitution p.Val73Met. This variant was reported in an individual with phaeochromocytoma/paraganglioma (Table S3, Ben Aim et al 2019. PubMed ID: 30877234). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184137/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.