Submissions for variant NM_000143.4(FH):c.6C>G (p.Tyr2Ter)

dbSNP: rs199971078

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002461294	SCV000632485	pathogenic	not provided	2024-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2*) 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 not present in population databases (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: 460375). 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	RCV000572622	SCV000673369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-30	criteria provided, single submitter	clinical testing	The p.Y2* alteration (also known as c.6C>G), located in coding exon 1 of the FH gene, results from a C to G substitution at nucleotide position 6. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theFH gene and 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 (Magrane M et al., Database (Oxford) 2011; bar009; Dik E et al. Traffic, 2016 Jul;17:720-32). 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 the 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.
GeneDx	RCV002461294	SCV002757675	likely pathogenic	not provided	2022-06-07	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27037871, 25913776, 21929734, 21447597, 20231875)
Baylor Genetics	RCV004568765	SCV005057780	likely pathogenic	Fumarase deficiency	2023-11-06	criteria provided, single submitter	clinical testing