chr1-241519722-T-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_000143.4(FH):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.000000719 in 1,391,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000143.4 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000682 AC: 1AN: 146594Hom.: 0 AF XY: 0.0000128 AC XY: 1AN XY: 78404
GnomAD4 exome AF: 7.19e-7 AC: 1AN: 1391288Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1AN XY: 685372
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 641546). 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. -
Fumarase deficiency Pathogenic:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.M1? variant (also known as c.1A>T), located in coding exon 1 of the FH gene, results from a A to T 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at