ClinVar Genomic variation as it relates to human health
NM_000137.4(FAH):c.709C>T (p.Arg237Ter)
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_000137.4(FAH):c.709C>T (p.Arg237Ter)
Variation ID: 437463 Accession: VCV000437463.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q25.1 15: 80173016 (GRCh38) [ NCBI UCSC ] 15: 80465358 (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 Aug 28, 2017 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000137.4:c.709C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000128.1:p.Arg237Ter nonsense NM_001374377.1:c.709C>T NP_001361306.1:p.Arg237Ter nonsense NM_001374380.1:c.709C>T NP_001361309.1:p.Arg237Ter nonsense NC_000015.10:g.80173016C>T NC_000015.9:g.80465358C>T NG_012833.1:g.25018C>T - Protein change
- R237*
- Other names
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- Canonical SPDI
- NC_000015.10:80173015:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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FAH | - | - |
GRCh38 GRCh37 |
699 | 767 |
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 (10) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000502414.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2021 | RCV001805120.4 |
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
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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
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000588377.2
First in ClinVar: Aug 28, 2017 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 2
Sex: male
Geographic origin: Iran
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163757.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(May 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370611.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: FAH c.709C>T (p.Arg237X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FAH c.709C>T (p.Arg237X) 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. The variant allele was found at a frequency of 1.2e-05 in 251496 control chromosomes. c.709C>T has been reported in the literature in multiple individuals affected with Tyrosinemia Type 1 (example, Suttiruk_2011, vanAmstel_1996, Rafati_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 03, 2021)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051611.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 12, 2022 |
Comment:
PVS1, PM2, PS3_Supporting
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841544.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000437463 / PMID: 8557261). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypertyrosinemia (present) , Multiple lentigines (present) , Failure to thrive (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003842245.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
A Heterozygous Splice site region, Nonsense variant c.709C>T in Exon 9 of the FAH gene that results in the amino acid substitution p.Arg237* was identified. … (more)
A Heterozygous Splice site region, Nonsense variant c.709C>T in Exon 9 of the FAH gene that results in the amino acid substitution p.Arg237* was identified. The observed variant has a minor allele frequency of 0.00001/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 437463). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047734.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop gained variant c.709C>T (p.Arg237Ter) in FAH gene has been observed to be homozygous in individuals affected with tyrosinemia (Jitraruch S et al., 2011). … (more)
The stop gained variant c.709C>T (p.Arg237Ter) in FAH gene has been observed to be homozygous in individuals affected with tyrosinemia (Jitraruch S et al., 2011). The p.Arg237Ter variant has allele frequency 0.001% in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Hepatomegaly (present)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001383279.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg237*) in the FAH gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg237*) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is present in population databases (rs769550316, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with tyrosinemia (PMID: 8557261, 22145516). ClinVar contains an entry for this variant (Variation ID: 437463). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804969.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Dec 30, 2017)
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no assertion criteria provided
Method: curation
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Tyrosinemia type I
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891638.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
Geographic origin: Middle East
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Pathogenic
(Sep 25, 2020)
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no assertion criteria provided
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002089833.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Prenatal Diagnosis of Tyrosinemia Type 1 Using Next Generation Sequencing. | Rafati M | Fetal and pediatric pathology | 2016 | PMID: 27093575 |
Long-term outcome of living donor liver transplantation in a Thai boy with hereditary tyrosinemia type I: a case report. | Jitraruch S | Journal of the Medical Association of Thailand = Chotmaihet thangphaet | 2011 | PMID: 22145516 |
Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries. | Bergman AJ | Human mutation | 1998 | PMID: 9633815 |
Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. | St-Louis M | Human mutation | 1997 | PMID: 9101289 |
Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship. | Ploos van Amstel JK | Human genetics | 1996 | PMID: 8557261 |
Text-mined citations for rs769550316 ...
HelpRecord last updated Apr 06, 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.