rs201502246
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_000143.4(FH):āc.908T>Cā(p.Leu303Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,904 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L303F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.908T>C | p.Leu303Ser | missense_variant | 7/10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.908T>C | p.Leu303Ser | missense_variant | 7/10 | 1 | NM_000143.4 | ENSP00000355518.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250126Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135404
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727124
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74392
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2024 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of pheochromocytoma whose tumor demonstrated loss of FH on immunohistochemistry testing and who also had a family history of renal cancer (PMID: 30050099); This variant is associated with the following publications: (PMID: 22595425, 22703879, 20549362, 30761759, 33052056, 35821608, 35993574, 36773955, 30050099) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 303 of the FH protein (p.Leu303Ser). This variant is present in population databases (rs201502246, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive fumarase deficiency and/or paraganglioma-pheochromocytoma syndrome (PMID: 22595425, 35821608; Invitae). ClinVar contains an entry for this variant (Variation ID: 41584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 22595425). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 09, 2022 | PP3, PM2 - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2024 | The p.L303S variant (also known as c.908T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 908. The leucine at codon 303 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified, in trans with another FH missense alteration, in a 12-year-old girl with mild fumarase deficiency (Kimonis VE et al. Mol. Genet. Metab. 2012 Sep;107:241-2). This variant has also been reported in an individual with an adrenal pheochromocytoma whose tumor demonstrated loss of heterozygosity of FH; this individual's father also had a history of renal cell carcinoma (Richter S et al. Genet. Med. 2018 Jul). Based on internal structural analysis, L303S is more disruptive to the central domain than several nearby internally pathogenic variants (Ambry internal data; Ajalla Aleixo MA et al. FEBS J 2019 05;286(10):1925-1940). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is expected to be causative of autosomal recessive FH deficiency when present along with a second likely pathogenic/pathogenic variant on the other allele; however, the clinical significance for autosomal dominant HLRCC is unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 26, 2024 | Variant summary: FH c.908T>C (p.Leu303Ser) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.908T>C has been reported in the literature in a compound heterozygous individual affected with fumarase deficiency (e.g. Kimonis_2012) and an individual affected with a pheochromocytoma with a father affected with renal cell carcinoma (e.g. Richter_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect on catalytic activity of this variant in vitro (e.g. Wilde_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22595425, 30050099, 37255402). ClinVar contains an entry for this variant (Variation ID: 41584). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Fumarase deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at