Submissions for variant NM_000143.4(FH):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs776806414

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498198	SCV000283670	likely pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FH mRNA. The next in-frame methionine is located at codon 44. 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 (no rsID available, gnomAD 0.009%). A different variant (c.1A>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 27037871). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 237113). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic for autosomal recessive fumarate hydratase deficiency. However, this variant is not likely to confer risk for autosomal dominant FH tumor predisposition syndrome.
GeneDx	RCV000498198	SCV000589882	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease but an alternate initiation codon at Met44 could serve as an in-frame site (Dik et al., 2016); Published functional studies demonstrate that when this alternate start codon is used there is aberrant localization of the FH protein exclusively to the cytosol, without any mitochondrial targeting (Dik et al., 2016); This variant is associated with the following publications: (PMID: 27037871)
Ambry Genetics	RCV002417984	SCV002724205	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the FH gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 44 amino acids from the initiation site. 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; bar009). 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 nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000498198	SCV002774597	uncertain significance	not provided	2021-08-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008182	SCV005639307	likely pathogenic	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2024-03-05	criteria provided, single submitter	clinical testing