ClinVar Genomic variation as it relates to human health
NM_000143.4(FH):c.703C>T (p.His235Tyr)
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.703C>T (p.His235Tyr)
Variation ID: 214376 Accession: VCV000214376.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 241508638 (GRCh38) [ NCBI UCSC ] 1: 241671938 (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 Jan 7, 2017 May 1, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000143.4:c.703C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000134.2:p.His235Tyr missense NC_000001.11:g.241508638G>A NC_000001.10:g.241671938G>A NG_012338.1:g.16117C>T LRG_504:g.16117C>T LRG_504t1:c.703C>T LRG_504p1:p.His235Tyr - Protein change
- H235Y
- Other names
- p.H235Y:CAT>TAT
- Canonical SPDI
- NC_000001.11:241508637:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000199454.7 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 1, 2021 | RCV002257492.4 |
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
(Sep 28, 2016)
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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: SCV000251420.8
First in ClinVar: Oct 11, 2015 Last updated: Jan 07, 2017 |
Comment:
The H235Y variant in the FH gene has previously been reported to segregate with disease in at least one family with hereditary leiomyomatosis and renal … (more)
The H235Y variant in the FH gene has previously been reported to segregate with disease in at least one family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kamai et al., 2012). The H235Y 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. The H235Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (H235R, H235D), as well as variants in nearby residues (K230R, R233C, R233L, R233H) have been reported in the Human Gene Mutation Database in association with FH-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, H235Y is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. (less)
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Likely pathogenic
(May 01, 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: SCV002535572.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The FH c.703C>T (p.H235Y) variant has been reported in heterozygosity in a large family meeting criteria for Hereditary Leiomyomatosis Renal Cell Carcinoma Syndrome (PMID: 23203078, … (more)
The FH c.703C>T (p.H235Y) variant has been reported in heterozygosity in a large family meeting criteria for Hereditary Leiomyomatosis Renal Cell Carcinoma Syndrome (PMID: 23203078, 26983443). This variant was found to segregate with the phenotype across 11 individuals in this family (PMID: 26983443). It is also known as c.574C>T, p.H192Y in the literature. This variant was observed in 1/18394 chromosomes in the East Asian population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 214376). 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 likely pathogenic. (less)
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Likely pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004218897.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000004 (1/251270 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been … (more)
The frequency of this variant in the general population, 0.000004 (1/251270 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an affected family with hereditary leiomyomatosis and renal cell cancer (PMIDs: 23203078 (2012) and 26983443 (2016)). In addition, a different variant at the same codon, c.704A>G (p.His235Arg), has been reported in individuals with HLRCC and shown to have reduced FH enzyme activity (PMID: 28300276 (2017)). 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, this variant is classified as likely pathogenic. (less)
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Pathogenic
(Jan 09, 2024)
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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: SCV004292024.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 235 of the FH protein (p.His235Tyr). … (more)
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 235 of the FH protein (p.His235Tyr). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with FH-related conditions (PMID: 23203078). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His192Tyr. ClinVar contains an entry for this variant (Variation ID: 214376). 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%. This variant disrupts the p.His235 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 15, 2019)
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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: SCV002662032.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.H235Y pathogenic mutation (also known as c.703C>T), located in coding exon 5 of the FH gene, results from a C to T substitution at … (more)
The p.H235Y pathogenic mutation (also known as c.703C>T), located in coding exon 5 of the FH gene, results from a C to T substitution at nucleotide position 703. The histidine at codon 235 is replaced by tyrosine, an amino acid with similar properties. This alteration, designated as C574T (H192Y), has been reported to segregate with disease in a Japanese family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kamai T et al. Int J Mol Sci, 2012 Nov;13:14518-32). Another alteration at this same position, c.704A>G (p.H235R), has been reported in two families with clinical diagnoses of HLRCC and functional analyses demonstrating reduced FH activity (Gardie B et al. J. Med. Genet. 2011 Apr;48(4):226-34; Muller M et al. Clin. Genet., 2017 Dec;92:606-615). 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 available evidence, this alteration is classified as a pathogenic 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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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 |
Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report. | Kamai T | BMC cancer | 2016 | PMID: 26983443 |
Protein profiling of blood samples from patients with hereditary leiomyomatosis and renal cell cancer by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. | Kamai T | International journal of molecular sciences | 2012 | PMID: 23203078 |
Text-mined citations for rs863223968 ...
HelpRecord last updated Sep 29, 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.