Submissions for variant NM_000143.4(FH):c.7C>T (p.Arg3Ter)

dbSNP: rs202166344

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196918	SCV000251442	pathogenic	not provided	2013-04-17	criteria provided, single submitter	clinical testing	The R3X nonsense mutation in the FH gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been reported previously to our knowledge, it is expected to be a pathogenic mutation. The variant is found in MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196918	SCV001417237	pathogenic	not provided	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3*) in the FH gene. FH has two initiator codons, p.Met1 and p.Met44, which result in two different functional isoforms that localize to the mitochondria and cytosol, respectively (PMID: 21929734, 27037871). Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). Variants affecting the mitochondrial isoform confer risk for fumarate hydratase deficiency, while variants that affect the cytosolic isoform confer risk for FH tumor predisposition syndrome. This variant is present in population databases (rs202166344, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 214391). This variant disrupts the mitochondria-targeting sequence (MTS) of the FH protein, which is important for protein import into the mitochondria (PMID: 27037871). This suggests that disruption of this region is causative of fumarate hydratase deficiency. For these reasons, this variant has been classified as Pathogenic for autosomal recessive fumarate hydratase deficiency. However, this variant is not likely to confer risk for autosomal dominant FH tumor predisposition syndrome.
Ambry Genetics	RCV002415845	SCV002678761	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-18	criteria provided, single submitter	clinical testing	The p.R3* variant (also known as c.7C>T), located in coding exon 1 of the FH gene, results from a C to T substitution at nucleotide position 7. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, there is a second in-frame methionine at p.M44. Proteins initiated from the first methionine are targeted to the mitochondrion while proteins initiated from the second methionine are targeted to the cytoplasm due to the lack of the mitochondrial targeting sequence encoded between them (Dik E et al. Traffic. 2016 Jul;17:720-32; Magrane M et al. Database (Oxford) 2011). Data suggest that it is the cytoplasmic protein that conveys the tumor suppressor function of FH (Yogev O et al. PLoS Biol. 2010 Mar;8:e1000328). This alteration and others that are expected to adversely affect the protein before the second methionine, have been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of HLRCC (Ambry internal data). The clinical impact of this variant in terms of autosomal recessive Fumarase Deficiency is also unclear due to the lack of this variant being associated with this autosomal recessive disease in the literature and internally. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003468886	SCV004197316	likely pathogenic	Fumarase deficiency	2024-03-27	criteria provided, single submitter	clinical testing