rs780001199
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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.671_672delβ(p.Glu224ValfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
FH
NM_000143.4 frameshift
NM_000143.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.78
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-241508668-ACT-A is Pathogenic according to our data. Variant chr1-241508668-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 16234.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.671_672del | p.Glu224ValfsTer25 | frameshift_variant | 5/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.671_672del | p.Glu224ValfsTer25 | frameshift_variant | 5/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461664Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727134
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FH are known to be pathogenic. This particular variant has been reported in two families affected with leiomyomatosis and renal cell cancer (PMID: 11865300, 21404119). This variant is also known as 2-bp del. in codon 181. This sequence change deletes 2 nucleotides from exon 5 of the FH mRNA (c.671_672delAG), causing a frameshift at codon 224. This creates a premature translational stop signal (p.Glu224Valfs*25) and is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2023 | This variant alters the translational reading frame of the FH mRNA and causes the premature termination of FH protein synthesis. In the published literature, this variant has been reported in multiple individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 34480341 (2021), 21404119 (2011)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Hereditary leiomyomatosis and renal cell cancer Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2002 | - - |
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