rs201532589
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_000143.4(FH):c.346A>T(p.Ile116Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,986 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).
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.346A>T | p.Ile116Phe | missense_variant | Exon 3 of 10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251458Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135898
GnomAD4 exome AF: 0.000112 AC: 163AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.0000935 AC XY: 68AN XY: 727192
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:5
PM2_moderate -
Not observed at 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 individuals with breast and other cancers, as well as an individual with pheochromocytoma/paraganglioma but also in unaffected controls (PMID: 28873162, 29684080, 36773955, 35441217); This variant is associated with the following publications: (PMID: 29684080, 28873162, 22703879, 36773955, 35441217, Melli2025[CaseReport]) -
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 116 of the FH protein (p.Ile116Phe). This variant is present in population databases (rs201532589, gnomAD 0.01%). This missense change has been observed in individual(s) with renal cancer (PMID: 35441217). ClinVar contains an entry for this variant (Variation ID: 41582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
The FH c.346A>T (p.Ile116Phe) variant has been reported in the published literature in individuals with renal cell carcinoma (PMID: 35441217 (2022)), paraganglioma (PGL) and pheochromocytoma (PCC) (PMID: 36773955 (2023)), unaffected individuals (PMID: 36773955 (2023)), and individuals undergoing genetic testing (PMIDs: 22703879 (2012), 28873162 (2017)). The frequency of this variant in the general population, 0.000077 (10/129168 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. -
- -
Fumarase deficiency Uncertain:3
- -
- -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
FH-related disorder Uncertain:1
The FH c.346A>T variant is predicted to result in the amino acid substitution p.Ile116Phe. This variant was reported in an individual with renal cell carcinoma (Supplementary Table 1B. Yngvadottir et al 2022. PubMed ID: 35441217). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has interpretations ranging from likely benign to uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41582/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary leiomyomatosis and renal cell cancer Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at