rs863224004
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000143.4(FH):c.1097G>A(p.Ser366Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,696 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S366S) 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.1097G>A | p.Ser366Asn | missense_variant | 7/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.1097G>A | p.Ser366Asn | missense_variant | 7/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461696Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727136
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 26, 2023 | The FH c.1097G>A (p.Ser366Asn) variant has been reported in the published literature in individuals with phenotypes associated with hereditary leiomyomatosis and renal cell cancer (HLRCC)(PMID: 12772087 (2003), 16237213 (2005), 21630274 (2011), 31299266 (2019)). Immunohistochemical analysis of tumors from patients with this variant showed loss of heterozygosity and were positive for (2-succinyl) cysteine (2SC) (termed protein succination) due to deficient fumarase (PMID: 21630274 (2011)). Additionally, this variant is predicted to alter the active site of the FH protein (PMID: 21445611 (2011), 12761039 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Also known as FH c.968G>A, p.Ser323Asn; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15937070, 12761039, 31299266, 18366737, 21630274, 12772087, 16597677, 16029320, 16237213, 21445611, 33237286) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 366 of the FH protein (p.Ser366Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple cutaneous and uterine leiomyomatosis (MCUL) or hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039, 12772087, 16237213; Invitae). This variant is also known as G968A or S323N. ClinVar contains an entry for this variant (Variation ID: 214419). 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. - |
Hereditary leiomyomatosis and renal cell cancer Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 17, 2023 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12761039, 31299266, 31831373, 21630274, 12772087]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 03, 2022 | The FH c.1097G>A (p.Ser366Asn) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been identified in multiple individuals with leiomyomas and/or renal cell carcinoma (PMID: 12761039, 12772087, 21630274). The tumors of at least three of these individuals also demonstrated loss of heterozygosity (PMID: 12761039, 21630274). In addition, immunohistochemical analysis of tumors from patients with this germline variant have shown an accumulation of succinated proteins as a result of fumarase deficiency (PMID: 21630274). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is also known as p.Ser323Asn in the literature. In summary, this variant meets criteria to be classified as likely pathogenic. - |
Fumarase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 22, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2023 | The p.S366N pathogenic mutation (also known as c.1097G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 1097. The serine at codon 366 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with multiple cutaneous and uterine leiyomyomatosis (Alam NA et al. J Mol Diagn. 2005 Oct;7:437-43; Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73:95-106; Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11; Gupta S et al. Hum Pathol, 2019 Sep;91:114-122; Ambry internal data). Immunohistochemical analysis of tumors in patients with the germline p.S366N mutation have shown that this alteration results in an accumulation of succinated proteins as a result of deficient fumarase; these patients' tumors also demonstrated loss of heterozygosity (Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11). In addition, the p.S366N variant has been predicted to alter the enzymatic active site of the FH protein (Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ajalla Aleixo MA et al. FEBS J. 2019 May;286:1925-1940; 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). Of note, this alteration is also designated as S323N (c.968G>A) in some published literature. 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