ClinVar Genomic variation as it relates to human health
NM_000143.4(FH):c.349G>C (p.Ala117Pro)
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.349G>C (p.Ala117Pro)
Variation ID: 265146 Accession: VCV000265146.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 241513632 (GRCh38) [ NCBI UCSC ] 1: 241676932 (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 Oct 10, 2016 May 1, 2024 Jul 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000143.4:c.349G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000134.2:p.Ala117Pro missense NC_000001.11:g.241513632C>G NC_000001.10:g.241676932C>G NG_012338.1:g.11123G>C LRG_504:g.11123G>C LRG_504t1:c.349G>C LRG_504p1:p.Ala117Pro P07954:p.Ala117Pro - Protein change
- A117P
- Other names
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- Canonical SPDI
- NC_000001.11:241513631:C: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 |
2027 | 2113 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 20, 2022 | RCV000255340.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2021 | RCV001020456.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 5, 2023 | RCV003456040.1 |
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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Pathogenic
(Dec 11, 2017)
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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: SCV000321640.6
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Comment:
The A117P missense variant in the FH gene has been reported previously in association with multiple leiomyomatosis (Tomlinson et al., 2002) and type 2 papillary … (more)
The A117P missense variant in the FH gene has been reported previously in association with multiple leiomyomatosis (Tomlinson et al., 2002) and type 2 papillary renal cell cancer (Gardie et al., 2011). The A117P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
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Pathogenic
(Jun 18, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535558.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The FH c.349G>C (p.A117P) variant has been reported in heterozygosity in multiple individuals with leiomyomas, renal cell cancer, or pheochromocytoma (PMID: 11865300, 21398687, 24334767, 31831373, … (more)
The FH c.349G>C (p.A117P) variant has been reported in heterozygosity in multiple individuals with leiomyomas, renal cell cancer, or pheochromocytoma (PMID: 11865300, 21398687, 24334767, 31831373, 33167498, among others). It is also known as c.220G>C (p.A74P) in the literature. This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) but has been reported in ClinVar (Variation ID: 265146). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Likely 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: SCV004187830.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24334767, 21398687, 11865300, 33167498, … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24334767, 21398687, 11865300, 33167498, 12761039]. Functional studies indicate this variant impacts protein function [PMID: 16237213]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Oct 20, 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: SCV001400741.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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. For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 11865300, 21398687). ClinVar contains an entry for this variant (Variation ID: 265146). This variant is also known as c.220G>C (p.Ala74Pro). This missense change has been observed in individual(s) with renal cell carcinoma and cutaneous and uterine leiomyomas and pheochromocytoma (PMID: 11865300, 21398687, 24334767, 31831373; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 117 of the FH protein (p.Ala117Pro). (less)
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Likely pathogenic
(Nov 09, 2020)
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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: SCV001181940.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.A117P variant (also known as c.349G>C), located in coding exon 3 of the FH gene, results from a G to C substitution at nucleotide … (more)
The p.A117P variant (also known as c.349G>C), located in coding exon 3 of the FH gene, results from a G to C substitution at nucleotide position 349. The alanine at codon 117 is replaced by proline, an amino acid with highly similar properties. This alteration has been described in several individuals with HLRCC (Tomlinson IP et al. Nat. Genet. 2002 Apr;30:406-10; Gardie B et al. J. Med. Genet. 2011 Apr;48:226-34; Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Ambry internal data). This alteration was also identified in a patient with a recurrent pheochromocytoma; she also had a hysterectomy at age 35 due to hemorrhagic fibroids (Letouzé E et al. Cancer Cell. 2013 Jun;23:739-52). 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 alteration is also called p.Ala74Pro in the literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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 Syndrome in Spain: Clinical and Genetic Characterization. | Sánchez-Heras AB | Cancers | 2020 | PMID: 33167498 |
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 |
Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. | Castro-Vega LJ | Human molecular genetics | 2014 | PMID: 24334767 |
SDH mutations establish a hypermethylator phenotype in paraganglioma. | Letouzé E | Cancer cell | 2013 | PMID: 23707781 |
Structural basis of fumarate hydratase deficiency. | Picaud S | Journal of inherited metabolic disease | 2011 | PMID: 21445611 |
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 |
Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. | Alam NA | The Journal of molecular diagnostics : JMD | 2005 | PMID: 16237213 |
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. | Alam NA | Human molecular genetics | 2003 | PMID: 12761039 |
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 rs886039363 ...
HelpRecord last updated Sep 01, 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.