rs1060500903
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000143.4(FH):βc.1347delβ(p.Met449IlefsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: not found (cov: 31)
Exomes π: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FH
NM_000143.4 frameshift
NM_000143.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.48
Genes affected
FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-241500479-TC-T is Pathogenic according to our data. Variant chr1-241500479-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 405924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.1347del | p.Met449IlefsTer5 | frameshift_variant | 9/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.1347del | p.Met449IlefsTer5 | frameshift_variant | 9/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727186
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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2
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1461784
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31
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0
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727186
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2016 | This truncation removes the last 56 amino acids (Met454-Lys510) from the full-length FH protein. A downstream truncating variant (p.Trp500*) deleting the last 11 amino acids has been observed in an individual with fumarate hydratase deficiency (PMID: 9635293, 20549362). It was also shown to segregate with disease in a large family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 21398687). In addition, another downstream truncation (p.Ala458Hisfs*10) that removes the last 53 amino acids of the FH protein has been classified as Likely Pathogenic at Invitae. This suggests that C-terminal truncation of FH is deleterious to protein function. This variant has been reported in the literature in an individual affected with multiple cutaneous and uterine leiomyomatosis (PMID: 11865300), and in a family with four affected members (PMID: 12761039). This variant is also known in the literature as 1-bp del. in codon 507. This sequence change deletes 1 nucleotide from exon 9 of the FH mRNA (c.1347delG), causing a frameshift at codon 449. This creates a premature translational stop signal in the previous to last exon of the FH mRNA (p.Met449Ilefs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 57 amino acids of the FH protein. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2023 | The c.1347delG pathogenic mutation, located in coding exon 9 of the FH gene, results from a deletion of one nucleotide at nucleotide position 1347, causing a translational frameshift with a predicted alternate stop codon (p.M449Ifs*5). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FH-related disease (Ambry internal data; Alam, NA et al. Hum Mol Genet 2003 Jun;12(11):1241-52; Forde, C et al. Eur Urol Oncol 2020 Dec;3(6):764-772). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at