rs863223965
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000143.4(FH):c.584T>C(p.Met195Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M195V) 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.584T>C | p.Met195Thr | missense_variant | 5/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.584T>C | p.Met195Thr | 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
Hereditary leiomyomatosis and renal cell cancer Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 16, 2022 | Variant summary: FH c.584T>C (p.Met195Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251158 control chromosomes. c.584T>C has been reported in the literature in multiple individuals affected with cutaneous leiomyomas, sporadic uterine fibroids, uterine leiomyoma and renal cell cancer, including an affected mother and son (e.g. Toro_2003, Kubinova_2013, Cunha_2018, Yonamine_2020, Zhang_2020). These data indicate that the variant is very likely to be associated with Hereditary Leiomyomatosis And Renal Cell Cancer. Additionally, a variant affecting the same codon has been reported in association with Leiomyomatosis and renal cell cancer (p.Met195Val). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 21, 2023 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22764886, 30171332, 32154112, 12772087]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 05-23-2016 by Lab Memorial Sloan-Kettering Department of Pathology. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the FH protein (p.Met195Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with uterine fibroids and hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087, 22764886; Invitae). This variant is also known as 455T>C (M152T). ClinVar contains an entry for this variant (Variation ID: 214373). 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%. Experimental studies have shown that this missense change affects FH function (PMID: 22764886). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 16029320, 21445611, 22473397, 12772087, 22764886, 16237213, 30171332, 29978187, 31444830, 28873162) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2024 | The p.M195T variant (also known as c.584T>C), located in coding exon 5 of the FH gene, results from a T to C substitution at nucleotide position 584. The methionine at codon 195 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in multiple individuals who have a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Kubinova K et al. J. Obstet. Gynaecol. Res., 2013 Jan;39:410-4; Tolvanen J et al. Hum. Reprod., 2012 Jun;27:1865-9; Yonamine T et al. Urol Case Rep, 2020 May;30:101141; Toro JR et al. Am. J. Hum. Genet., 2003 Jul;73:95-106; Carlo MI et al. JAMA Oncol, 2018 09;4:1228-1235). Another variant at the same codon, p.M195V (c.583A>G), has been observed in individuals with a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Tolvanen J et al. Hum Reprod, 2012 Jun;27:1865-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at