Submissions for variant NM_000143.4(FH):c.65T>A (p.Leu22Ter)

dbSNP: rs1031919395

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001771965	SCV000823616	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	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 hereditary leiomyomatosis and renal cell cancer. 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. ClinVar contains an entry for this variant (Variation ID: 573460). This variant has not been reported in the literature in individuals affected with FH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu22*) 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 hereditary leiomyomatosis and renal cell cancer.
GeneDx	RCV001771965	SCV001992784	uncertain significance	not provided	2019-06-19	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21929734, 27037871)
Ambry Genetics	RCV003163189	SCV003866372	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	The p.L22* variant (also known as c.65T>A), located in coding exon 1 of the FH gene, results from a T to A substitution at nucleotide position 65. This changes the amino acid from a leucine 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). Alterations 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	RCV003460938	SCV004197371	likely pathogenic	Fumarase deficiency	2023-03-20	criteria provided, single submitter	clinical testing