ClinVar Genomic variation as it relates to human health
NM_000143.4(FH):c.584T>C (p.Met195Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000143.4(FH):c.584T>C (p.Met195Thr)
Variation ID: 214373 Accession: VCV000214373.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 241508757 (GRCh38) [ NCBI UCSC ] 1: 241672057 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 30, 2017 Aug 11, 2024 Apr 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000143.4:c.584T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000134.2:p.Met195Thr missense NC_000001.11:g.241508757A>G NC_000001.10:g.241672057A>G NG_012338.1:g.15998T>C LRG_504:g.15998T>C LRG_504t1:c.584T>C LRG_504p1:p.Met195Thr - Protein change
- M195T
- Other names
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- Canonical SPDI
- NC_000001.11:241508756:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FH | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2029 | 2115 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000505795.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV002222438.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2024 | RCV002354552.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jan 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000251415.7
First in ClinVar: Oct 11, 2015 Last updated: Sep 30, 2017 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Mar 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary leiomyomatosis and renal cell cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500416.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000821377.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Apr 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002648423.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary leiomyomatosis and renal cell cancer
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004933807.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
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]. … (more)
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]. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary leiomyomatosis and renal cell cancer
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228486.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Renal cell carcinoma (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Memorial Sloan-Kettering Department of Pathology
Date variant was reported to submitter: 2016-05-23
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary leiomyomatosis and renal cell cancer (HLRCC): A case report. | Yonamine T | Urology case reports | 2020 | PMID: 32154112 |
Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. | Zhang L | Human mutation | 2020 | PMID: 31444830 |
Expanding morphological and clinical aspects of hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a case report in a patient with unusual morphology and clinical presentation. | da Cunha IW | Virchows Archiv : an international journal of pathology | 2018 | PMID: 30171332 |
Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. | Carlo MI | JAMA oncology | 2018 | PMID: 29978187 |
Fumarate hydratase gene mutation in two young patients with sporadic uterine fibroids. | Kubinova K | The journal of obstetrics and gynaecology research | 2013 | PMID: 22764886 |
Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. | Tolvanen J | Human reproduction (Oxford, England) | 2012 | PMID: 22473397 |
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. | Toro JR | American journal of human genetics | 2003 | PMID: 12772087 |
Text-mined citations for rs863223965 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.