ClinVar Genomic variation as it relates to human health
NM_000143.4(FH):c.395_399del (p.Lys131_Leu132insTer)
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.395_399del (p.Lys131_Leu132insTer)
Variation ID: 214408 Accession: VCV000214408.14
- Type and length
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Microsatellite, 5 bp
- Location
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Cytogenetic: 1q43 1: 241512123-241512127 (GRCh38) [ NCBI UCSC ] 1: 241675423-241675427 (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 Mar 19, 2017 May 1, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000143.4:c.395_399del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000134.2:p.Lys131_Leu132insTer nonsense NM_000143.3:c.395_399delTAAAT NC_000001.11:g.241512123ATTTA[1] NC_000001.10:g.241675423ATTTA[1] NG_012338.1:g.12623TAAAT[1] LRG_504:g.12623TAAAT[1] LRG_504t1:c.395_399del - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:241512122:ATTTAATTTA:ATTTA
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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
Help
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 |
1967 | 2051 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 11, 2023 | RCV000195662.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 5, 2023 | RCV000445600.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV004020397.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
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
Help
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
Help
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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Pathogenic
(Jan 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary leiomyomatosis and renal cell cancer
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000537228.1
First in ClinVar: Mar 19, 2017 Last updated: Mar 19, 2017
Comment:
Clinical Testing
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Number of individuals with the variant: 2
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Pathogenic
(Aug 11, 2023)
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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: SCV000251464.13
First in ClinVar: Oct 11, 2015 Last updated: Aug 24, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with HLRCC in published literature (Muller et al., 2017); This variant is associated with the following publications: (PMID: 26900816, 33313134, 31831373, 28300276) (less)
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Pathogenic
(Nov 10, 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: SCV002765932.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: FH c.395_399delTAAAT (p.Leu132X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FH c.395_399delTAAAT (p.Leu132X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and associated with Leiomyomatosis and Renal Cell Cancer in HGMD. The variant was absent in 250762 control chromosomes. c.395_399delTAAAT has been reported in the literature in individuals affected with Hereditary Leiomyomatosis And Renal Cell Cancer (Muller_2017 and Forde_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 05, 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: SCV004187919.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Nov 07, 2022)
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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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Invitae
Accession: SCV001380195.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu132*) in the FH gene. … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu132*) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of hereditary leiomyomatosis and renal cell carcinoma syndrome (PMID: 28300276). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 214408). (less)
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Pathogenic
(Jan 16, 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: SCV005032736.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.395_399delTAAAT pathogenic mutation, located in coding exon 4 of the FH gene, results from a deletion of 5 nucleotides at nucleotide positions 395 to … (more)
The c.395_399delTAAAT pathogenic mutation, located in coding exon 4 of the FH gene, results from a deletion of 5 nucleotides at nucleotide positions 395 to 399, causing a translational frameshift with a predicted alternate stop codon (p.L132*). This variant has been identified in a French HLRCC cohort (Muller M et al. Clin Genet, 2017 Dec;92:606-615). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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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: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals. | Forde C | European urology oncology | 2020 | PMID: 31831373 |
Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. | Muller M | Clinical genetics | 2017 | PMID: 28300276 |
Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. | Gardie B | Journal of medical genetics | 2011 | PMID: 21398687 |
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. | Tomlinson IP | Nature genetics | 2002 | PMID: 11865300 |
Text-mined citations for rs863223995 ...
HelpRecord last updated May 12, 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.