rs1060500900
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_000143.4(FH):c.40_41insC(p.Leu14ProfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 1,546,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.
Frequency
Consequence
NM_000143.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.40_41insC | p.Leu14ProfsTer42 | frameshift_variant | 1/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.40_41insC | p.Leu14ProfsTer42 | frameshift_variant | 1/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000275 AC: 4AN: 145674Hom.: 0 AF XY: 0.0000256 AC XY: 2AN XY: 78044
GnomAD4 exome AF: 0.0000416 AC: 58AN: 1394794Hom.: 0 Cov.: 31 AF XY: 0.0000422 AC XY: 29AN XY: 687692
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Nonsense variant in a gene for which loss-of-function is a known mechanism of disease; however, a downstream in-frame ATG could serve as an alternate initiator codon (Dik et al., 2016); Observed in an individual with a head and neck paraganglioma, and another with an isolated cutaneous leiomyosarcoma and reduced FH enzyme activity (Weiler et al., 2016; Parisien-La Salle et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28300276, 33084842, 27037871, 25913776, 34750850) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Leu14Profs*42) 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 present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a primary cutaneous leiomyosarcoma (PMID: 25913776). ClinVar contains an entry for this variant (Variation ID: 405920). 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. - |
Fumarase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.40dupC variant, located in coding exon 1 of the FH gene, results from a duplication of C at nucleotide position 40, causing a translational frameshift with a predicted alternate stop codon (p.L14Pfs*42). 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; 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 alteration was detected in an individual with a single cutaneous leiomyoma and two small uterine fibroids at age 72, whose father had kidney cancer diagnosed at age 58. Of note, this patient had 45% fumarase activity in her blood (Weiler L et al. Br. J. Dermatol., 2015 Apr;175:1104-06). This variant, designated as c.40dup (p.Leu14fs) has been reported in a French cohort of individuals with HLRCC (Muller M et al. Clin Genet, 2017 Dec;92:606-615). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at