rs75086406
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000143.4(FH):c.302G>C(p.Arg101Pro) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101Q) has been classified as Likely benign.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.302G>C | p.Arg101Pro | missense_variant | 3/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.302G>C | p.Arg101Pro | missense_variant | 3/10 | 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:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 101 of the FH protein (p.Arg101Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant FH-related conditions (PMID: 15663510, 17908262). It has also been observed to segregate with disease in related individuals. This variant is also known as R58P. ClinVar contains an entry for this variant (Variation ID: 16238). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2017 | The R101P variant in the FH gene has previously been reported to segregate with disease in at least one large family with hereditary leiomyomatosis and renal cell cancer (Chan et al., 2005; Heinritz et al., 2008). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R101P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available evidence, R101P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. - |
Hereditary leiomyomatosis and renal cell cancer Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2024 | The p.R101P pathogenic mutation (also known as c.302G>C), located in coding exon 3 of the FH gene, results from a G to C substitution at nucleotide position 302. The arginine at codon 101 is replaced by proline, an amino acid with dissimilar properties. This mutation, designated R58P (c.173G>C), has been shown to segregate with disease in multiple individuals with features of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in a large Polish family (Chan I et al. Clin. Exp. Dermatol., 2005 Jan;30:75-8; Heinritz W et al. Ann. Hum. Genet., 2008 Jan;72:35-40). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at