rs201261794
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1PS1_ModeratePP3PP5BS2
The NM_000143.4(FH):āc.2T>Gā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000454 in 1,543,494 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
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000036 ( 0 hom. )
Consequence
FH
NM_000143.4 start_lost
NM_000143.4 start_lost
Scores
7
6
3
Clinical Significance
Conservation
PhyloP100: 4.81
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000143.4 (FH) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1502868
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-241519721-A-C is Pathogenic according to our data. Variant chr1-241519721-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429172.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
BS2
?
High AC in GnomAdExome4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.2T>G | p.Met1? | start_lost | 1/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.2T>G | p.Met1? | start_lost | 1/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000206 AC: 3AN: 145704Hom.: 0 AF XY: 0.0000256 AC XY: 2AN XY: 77986
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GnomAD4 exome AF: 0.00000359 AC: 5AN: 1391322Hom.: 0 Cov.: 31 AF XY: 0.00000584 AC XY: 4AN XY: 685408
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | Initiation codon variant in a gene for which loss of function is a known mechanism of disease but an alternate initiation codon at Met44 could serve as an in-frame site (Dik et al., 2016); Published functional studies of other variants affecting Met1 have demonstrated that when this alternate start codon is used, fumarase enzyme activity is comparable to wild-type; however, there is aberrant localization of the FH protein exclusively to the cytosol, without any mitochondrial targeting (Stein et al., 1994; Sass et al., 2001; Dik et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21447597, 27037871, 8007976, 11585823, 21398687, 20231875, 11865300) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | 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 0.01%). 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: 429172). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2023 | The p.M1? variant (also known as c.2T>G), located in coding exon 1 of the FH gene, results from a T to G substitution at nucleotide position 2. 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 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of methylation at M1 (P = 0.0052);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at