Submissions for variant NM_000143.4(FH):c.1A>C (p.Met1Leu)

dbSNP: rs776806414

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000307949	SCV000356751	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000369616	SCV000356752	uncertain significance	Fumarase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000307949	SCV000356753	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002522126	SCV001415133	likely pathogenic	not provided	2024-10-09	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 0.004%). 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: 296878). 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.
Ambry Genetics	RCV002418146	SCV002724197	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the FH gene, results from a A to C 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000369616	SCV005399034	likely pathogenic	Fumarase deficiency	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fumarase deficiency (MIM#606812) and leiomyomatosis and renal cell cancer (MIM#150800). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Autosomal dominant hereditary leiomyomatosis and renal cell cancer (MIM#150800) has been associated with the cytosolic isoform (PMIDs: 20231875, 21398687, 28300276). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). The first 43 amino acid residues encode the mitochondrial targeting sequence, followed by an alternative initiation codon p.Met44 (PMID: 27037871). This variant is expected to affect the mitochondrial isoform, but not the cytosolic isoform. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0708 - Other start-loss variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Met1Val), p.(Met1Leu), p.(Met1Arg), p.(Met1Thr) and p.(Met1Lys) have been classified as both likely pathogenic and variants of uncertain significance, and p.(Met1Ile) has been classified as likely pathogenic by clinical laboratories (ClinVar). In addition, p.(Met1Val) has been reported once in a heterozygous individual with urothelial carcinoma without renal cell carcinoma (PMID: 31844177). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported twice as likely pathogenic and twice as a variant of uncertain significance by clinical laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005008276	SCV005639318	likely pathogenic	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2024-04-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000369616	SCV002085917	likely pathogenic	Fumarase deficiency	2020-09-01	no assertion criteria provided	clinical testing