rs1131691238
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000143.4(FH):c.1094G>A(p.Ser365Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,732 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S365G) has been classified as Likely pathogenic.
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.1094G>A | p.Ser365Asn | missense_variant | 7/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.1094G>A | p.Ser365Asn | missense_variant | 7/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461732Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727144
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser365 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12772087, 22243733, 22565324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 429174). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer syndrome (PMID: 31831373; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 365 of the FH protein (p.Ser365Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 12, 2024 | The p.S365N variant (also known as c.1094G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 1094. The serine at codon 365 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals meeting clinical diagnostic criteria for HLRCC (Ambry internal data; Forde C et al. Eur Urol Oncol, 2020 Dec;3:764-772). Internal structural analysis indicates that this variant disrupts a specific protein-ligand interaction involved with fumarate-binding and protein function (Ambry internal data; Pereira de Pádua RA et al. Acta Crystallogr F Struct Biol Commun, 2014 Jan;70:120-2; Mechaly AE et al. FEBS Lett., 2012 Jun;586:1606-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at