rs863223967
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000143.4(FH):c.688A>G(p.Lys230Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K230R) has been classified as Pathogenic.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.688A>G | p.Lys230Glu | missense_variant | 5/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.688A>G | p.Lys230Glu | missense_variant | 5/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 230 of the FH protein (p.Lys230Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 29423582, 31182090). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214375). 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%. This variant disrupts the p.Lys230 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9635293, 11865300, 12761039, 12772087, 16206287, 19470762, 26574848). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at