ClinVar Genomic variation as it relates to human health
NM_000137.4(FAH):c.1027G>T (p.Gly343Trp)
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.1027G>T (p.Gly343Trp)
Variation ID: 576751 Accession: VCV000576751.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q25.1 15: 80180190 (GRCh38) [ NCBI UCSC ] 15: 80472532 (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, 2018 Jun 17, 2024 Mar 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000137.4:c.1027G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000128.1:p.Gly343Trp missense NM_001374377.1:c.1027G>T NP_001361306.1:p.Gly343Trp missense NM_001374380.1:c.1027G>T NP_001361309.1:p.Gly343Trp missense NC_000015.10:g.80180190G>T NC_000015.9:g.80472532G>T NG_012833.1:g.32192G>T - Protein change
- G343W
- Other names
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- Canonical SPDI
- NC_000015.10:80180189:G: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00012
- Links
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 |
714 | 782 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2018 | RCV000733554.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2024 | RCV000699322.12 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Jun 04, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000861633.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 27, 2024)
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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: SCV000828027.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the FAH protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the FAH protein (p.Gly343Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 12203990; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 576751). 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 FAH protein function with a positive predictive value of 80%. This variant disrupts the p.Gly343 amino acid residue in FAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21764616). 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
(Mar 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001163763.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816171.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 11, 2024)
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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: SCV004804388.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: FAH c.1027G>T (p.Gly343Trp) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domian (IPR011234) of the encoded protein sequence. Five … (more)
Variant summary: FAH c.1027G>T (p.Gly343Trp) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domian (IPR011234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247234 control chromosomes (gnomAD). c.1027G>T has been reported in the literature in multiple individuals affected with Tyrosinemia Type 1 (Arranz_2002, Couce_2011, Couce_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant effect results in 11% of normal activity (Macias_2019). The following publications have been ascertained in the context of this evaluation (PMID: 12203990, 31574857, 21752152, 35800472, 31300554, NO_PMID). ClinVar contains an entry for this variant (Variation ID: 576751). Based on the evidence outlined above, the variant was classified as 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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A case report of two siblings with hypertyrosinemia type 1 presenting with hepatic disease with different onset time and severity. | Kawabata K | Molecular genetics and metabolism reports | 2022 | PMID: 35800472 |
Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain. | Couce ML | Medicine | 2019 | PMID: 31574857 |
Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate. | Macias I | The Journal of biological chemistry | 2019 | PMID: 31300554 |
Identification of mutations causing hereditary tyrosinemia type I in patients of Middle Eastern origin. | Imtiaz F | Molecular genetics and metabolism | 2011 | PMID: 21764616 |
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome. | Couce ML | Pediatrics international : official journal of the Japan Pediatric Society | 2011 | PMID: 21752152 |
Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients. | Arranz JA | Human mutation | 2002 | PMID: 12203990 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FAH | - | - | - | - |
Text-mined citations for rs970505762 ...
HelpRecord last updated Jun 17, 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.