The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud 2012, Mayorandan 2014, and Mannion 2016). This variant has also been rep orted in ClinVar (Variation ID#11870) by multiple laboratories as pathogenic. Th is variant has been identified in 0.065% (41/63,022) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 80338901). In vitro splicing assays provide evidence that the c.1062+5G>A varian t impacts splicing (Perez-Carro 2014). Biallelic loss of function of the FAH gen e has been associated with Tyrosinemia type I. In summary, this variant meets c riteria to be classified as pathogenic for Tyrosinemia type I in an autosomal re cessive manner based upon functional evidence and its occurrence in individuals with this disease.
ClinVar Genomic variation as it relates to human health
NM_000137.4(FAH):c.1062+5G>A
Germline
Classification
Help
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.
(28)
Help
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.
Pathogenic
28
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000137.4(FAH):c.1062+5G>A
Variation ID: 11870 Accession: VCV000011870.77
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q25.1 15: 80180230 (GRCh38) [ NCBI UCSC ] 15: 80472572 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Oct 20, 2024 Mar 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000137.4:c.1062+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001374377.1:c.1062+5G>A intron variant NM_001374380.1:c.1062+5G>A intron variant NC_000015.10:g.80180230G>A NC_000015.9:g.80472572G>A NG_012833.1:g.32232G>A - Protein change
- -
- Other names
-
IVS12+5 G>A
IVS12DS, G-A, +5
- Canonical SPDI
- NC_000015.10:80180229:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00042
Trans-Omics for Precision Medicine (TOPMed) 0.00023
The Genome Aggregation Database (gnomAD) 0.00028
The Genome Aggregation Database (gnomAD), exomes 0.00037
1000 Genomes Project 30x 0.00062
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| FAH | - | - |
GRCh38 GRCh37 |
718 | 786 | |
Conditions - Germline
| Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (18) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000012645.50 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000078135.45 | |
|
FAH-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 22, 2023 | RCV003407317.5 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000109973.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Pathogenic
(Apr 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713107.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud … (more)
The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud 2012, Mayorandan 2014, and Mannion 2016). This variant has also been rep orted in ClinVar (Variation ID#11870) by multiple laboratories as pathogenic. Th is variant has been identified in 0.065% (41/63,022) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 80338901). In vitro splicing assays provide evidence that the c.1062+5G>A varian t impacts splicing (Perez-Carro 2014). Biallelic loss of function of the FAH gen e has been associated with Tyrosinemia type I. In summary, this variant meets c riteria to be classified as pathogenic for Tyrosinemia type I in an autosomal re cessive manner based upon functional evidence and its occurrence in individuals with this disease. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329344.7
First in ClinVar: Dec 06, 2016 Last updated: Dec 03, 2022 |
Comment:
Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional … (more)
Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); This variant is associated with the following publications: (PMID: 26565546, 8028615, 27876694, 25087612, 23895425, 22975760, 25525159, 8318997, 27794060, 29497141, 29326876, 30414057, 30609409, 31568711, 34426522, 31589614, 33083013, 11754109, 9705236) (less)
|
|
|
Pathogenic
(May 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893383.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
FAH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113967.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred … (more)
The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred to as IVS12+5G>A; Grompe and al-Dhalimy. 1993. PubMed ID: 8318997; Pérez-Carro et al. 2014. PubMed ID: 23895425) and is particularly prevalent in the French Canadian and Northern European populations (Poudrier et al. 1996. PubMed ID: 8821854; Sheth et al. 2012. PubMed ID: 23193487). Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425). This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11870/). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80472572-G-A). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000826047.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. … (more)
This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338901, gnomAD 0.07%). This variant has been observed in individuals with hereditary tyrosinemia type 1 (PMID: 8318997, 23895425, 26565546). It is commonly reported in individuals of French-Canadian ancestry (PMID: 23193487, 28755192). ClinVar contains an entry for this variant (Variation ID: 11870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004698117.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Comment:
Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4
Clinical Features:
Hypertyrosinemia (present)
Sex: male
|
|
|
Pathogenic
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695441.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome … (more)
Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001). The variant of interest has been found in a large and broad control population from ExAC in 48/114466 control chromosomes at an allele frequency of 0.0004193, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant is a known common pathogenic variant that causes tyrosinemia type I and is more commonly found in French Canadian population than the rest of the world (Grompe_1994; GeneReviews). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000394056.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in … (more)
The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in at least nine studies in which it is found in a total of 336 patients, including in 47 patients in a homozygous state, in five patients in a compound heterozygous state and in 15 patients in a heterozygous state. The c.1062+5G>A variant was also detected in 11/395 blood spots from anonymous newborns from the Quebec area (Grompe et al. 1993; Grompe et al. 1994; St-Louis et al. 1995; Poudrier et al. 1996; Bergman et al. 1998; Elpeleg et al. 2002; Arranz et al. 2002; Perez-Carro et al. 2014; Mayorandan et al. 2014). The incidence of tyrosinemia is much higher in the Saguenay-Lac-St-Jean region of Quebec than in the rest of the world. In this region the c.1062+5G>A variant was detected in 62/68 patient alleles, and in 86/180 obligate carrier alleles (Grompe et al. 1994; Poudrier et al. 1996). The c.1062+5G>A variant was absent from 91 healthy controls and is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998). Based on the collective evidence, the c.1062+5G>A variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193867.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, … (more)
NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, 8821854, 8829657 and 8028615. Classification of NM_000137.2(FAH):c.1062+5G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424411.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
|
|
|
Pathogenic
(Aug 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715123.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PM1, PM2, PP3, PP5
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073255.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin … (more)
Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin GA et al). Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R). The variant has been submitted to ClinVar as Pathogenic. Due to the above reasons it has been classified as Pathogenic. (less)
Clinical Features:
Hepatomegaly (present) , Thrombocytopenia (present) , Decreased circulating ceruloplasmin concentration (present) , Decreased circulating copper concentration (present)
|
|
|
Pathogenic
(Dec 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746930.2
First in ClinVar: Apr 09, 2018 Last updated: Dec 11, 2022 |
Age: 30-39 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818245.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004013440.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
|
|
|
Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004026906.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
|
Pathogenic
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022273.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163764.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086468.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosinemia, type I, (MIM#276700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of Hep3B cells transfected with a minigene assay indicates that this variant causes exon 12 skipping, although additional products were observed. Due to these products, and the uncertainty regarding the use of minigene assays, the protein outcome of this splicing event is uncertain (PMID: 23895425). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (102 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both homozygous and compound heterozygous individuals with hereditary tyrosinemia (ClinVar, PMID: 30414057. PMID: 31574857). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249202.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
FAH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jun 01, 1998)
|
no assertion criteria provided
Method: literature only
|
TYROSINEMIA, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032880.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 02, 2015 |
Comment on evidence:
In a patient from eastern Quebec with tyrosinemia type I (TYRSN1; 276700), Grompe and Al-Dhalimy (1993) demonstrated homozygosity for a splice mutation consisting of a … (more)
In a patient from eastern Quebec with tyrosinemia type I (TYRSN1; 276700), Grompe and Al-Dhalimy (1993) demonstrated homozygosity for a splice mutation consisting of a guanine-to-adenine alteration in the donor consensus sequence of intron 12 (IVS12+5G-A) of the FAH gene. Two other mutations, glu357-to-ter (E357X) and glu364-to-ter (E364X), were identified. Grompe et al. (1994) designed allele-specific oligonucleotide tests to detect the 3 mutations and used them to demonstrate that all patients with tyrosinemia type I in eastern Quebec carried the splice-donor site mutation, most of them in homozygous state. St-Louis et al. (1995) found the same mutation in a compound heterozygous Norwegian patient. The fact that this is the predominant mutation in French Canadian cases (having a frequency of 77.6% among Quebec patients with tyrosinemia type I) may indicate its ancient origin. The other mutation in the Norwegian patient was G337S (613871.0007). The 2 extremes of the clinical phenotype of tyrosinemia type I are the 'acute' (a severe disorder with early onset and death), and 'chronic' (showing delayed onset and slow course) forms. Allelic heterogeneity and/or mutation reversion in hepatic cells had been proposed to explain the clinical heterogeneity. Poudrier et al. (1998) studied 2 probands from the French Canadian isolate where type I tyrosinemia is prevalent, one with the acute and the other with the chronic form. Both were found to be germline homozygotes for the IVS12+5G-A splice site mutation. Both showed liver mosaicism for FAH immunoreactivity with evidence for mutation reversion to heterozygosity in FAH-stained nodules as shown by amplification of DNA extracted from microdissected nodules. Western blot analysis of proteins from a reverted FAH-expressing nodule showed 29 +/- 3% FAH immunoreactive material as compared to an average normal liver. This was consistent with the measured FAH hydrolytic activity (25%) in this large regenerating nodule. These findings showed that genotypic heterogeneity is not a sufficient explanation for clinical heterogeneity and implicated epigenetic and other factors modifying the phenotype in this disorder. (less)
|
|
|
Pathogenic
(Dec 30, 2017)
|
no assertion criteria provided
Method: curation
|
Tyrosinemia type I
Affected status: yes
Allele origin:
unknown
|
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891501.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Geographic origin: Middle East
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454599.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742656.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554003.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953339.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040448.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Ethnicity/Population group: Northern European, French Canadian
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Comment:
Comment:
Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); This variant is associated with the following publications: (PMID: 26565546, 8028615, 27876694, 25087612, 23895425, 22975760, 25525159, 8318997, 27794060, 29497141, 29326876, 30414057, 30609409, 31568711, 34426522, 31589614, 33083013, 11754109, 9705236)
Comment:
The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred to as IVS12+5G>A; Grompe and al-Dhalimy. 1993. PubMed ID: 8318997; Pérez-Carro et al. 2014. PubMed ID: 23895425) and is particularly prevalent in the French Canadian and Northern European populations (Poudrier et al. 1996. PubMed ID: 8821854; Sheth et al. 2012. PubMed ID: 23193487). Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425). This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11870/). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80472572-G-A). This variant is interpreted as pathogenic.
Comment:
This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338901, gnomAD 0.07%). This variant has been observed in individuals with hereditary tyrosinemia type 1 (PMID: 8318997, 23895425, 26565546). It is commonly reported in individuals of French-Canadian ancestry (PMID: 23193487, 28755192). ClinVar contains an entry for this variant (Variation ID: 11870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4
Comment:
Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001). The variant of interest has been found in a large and broad control population from ExAC in 48/114466 control chromosomes at an allele frequency of 0.0004193, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant is a known common pathogenic variant that causes tyrosinemia type I and is more commonly found in French Canadian population than the rest of the world (Grompe_1994; GeneReviews). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in at least nine studies in which it is found in a total of 336 patients, including in 47 patients in a homozygous state, in five patients in a compound heterozygous state and in 15 patients in a heterozygous state. The c.1062+5G>A variant was also detected in 11/395 blood spots from anonymous newborns from the Quebec area (Grompe et al. 1993; Grompe et al. 1994; St-Louis et al. 1995; Poudrier et al. 1996; Bergman et al. 1998; Elpeleg et al. 2002; Arranz et al. 2002; Perez-Carro et al. 2014; Mayorandan et al. 2014). The incidence of tyrosinemia is much higher in the Saguenay-Lac-St-Jean region of Quebec than in the rest of the world. In this region the c.1062+5G>A variant was detected in 62/68 patient alleles, and in 86/180 obligate carrier alleles (Grompe et al. 1994; Poudrier et al. 1996). The c.1062+5G>A variant was absent from 91 healthy controls and is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998). Based on the collective evidence, the c.1062+5G>A variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, 8821854, 8829657 and 8028615. Classification of NM_000137.2(FAH):c.1062+5G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
PS3, PM1, PM2, PP3, PP5
Comment:
Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin GA et al). Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R). The variant has been submitted to ClinVar as Pathogenic. Due to the above reasons it has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosinemia, type I, (MIM#276700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of Hep3B cells transfected with a minigene assay indicates that this variant causes exon 12 skipping, although additional products were observed. Due to these products, and the uncertainty regarding the use of minigene assays, the protein outcome of this splicing event is uncertain (PMID: 23895425). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (102 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both homozygous and compound heterozygous individuals with hereditary tyrosinemia (ClinVar, PMID: 30414057. PMID: 31574857). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
FAH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Comment:
Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
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. |
Comment:
The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud 2012, Mayorandan 2014, and Mannion 2016). This variant has also been rep orted in ClinVar (Variation ID#11870) by multiple laboratories as pathogenic. Th is variant has been identified in 0.065% (41/63,022) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 80338901). In vitro splicing assays provide evidence that the c.1062+5G>A varian t impacts splicing (Perez-Carro 2014). Biallelic loss of function of the FAH gen e has been associated with Tyrosinemia type I. In summary, this variant meets c riteria to be classified as pathogenic for Tyrosinemia type I in an autosomal re cessive manner based upon functional evidence and its occurrence in individuals with this disease.
Comment:
Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); This variant is associated with the following publications: (PMID: 26565546, 8028615, 27876694, 25087612, 23895425, 22975760, 25525159, 8318997, 27794060, 29497141, 29326876, 30414057, 30609409, 31568711, 34426522, 31589614, 33083013, 11754109, 9705236)
Comment:
The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred to as IVS12+5G>A; Grompe and al-Dhalimy. 1993. PubMed ID: 8318997; Pérez-Carro et al. 2014. PubMed ID: 23895425) and is particularly prevalent in the French Canadian and Northern European populations (Poudrier et al. 1996. PubMed ID: 8821854; Sheth et al. 2012. PubMed ID: 23193487). Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425). This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11870/). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80472572-G-A). This variant is interpreted as pathogenic.
Comment:
This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338901, gnomAD 0.07%). This variant has been observed in individuals with hereditary tyrosinemia type 1 (PMID: 8318997, 23895425, 26565546). It is commonly reported in individuals of French-Canadian ancestry (PMID: 23193487, 28755192). ClinVar contains an entry for this variant (Variation ID: 11870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4
Comment:
Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001). The variant of interest has been found in a large and broad control population from ExAC in 48/114466 control chromosomes at an allele frequency of 0.0004193, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant is a known common pathogenic variant that causes tyrosinemia type I and is more commonly found in French Canadian population than the rest of the world (Grompe_1994; GeneReviews). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in at least nine studies in which it is found in a total of 336 patients, including in 47 patients in a homozygous state, in five patients in a compound heterozygous state and in 15 patients in a heterozygous state. The c.1062+5G>A variant was also detected in 11/395 blood spots from anonymous newborns from the Quebec area (Grompe et al. 1993; Grompe et al. 1994; St-Louis et al. 1995; Poudrier et al. 1996; Bergman et al. 1998; Elpeleg et al. 2002; Arranz et al. 2002; Perez-Carro et al. 2014; Mayorandan et al. 2014). The incidence of tyrosinemia is much higher in the Saguenay-Lac-St-Jean region of Quebec than in the rest of the world. In this region the c.1062+5G>A variant was detected in 62/68 patient alleles, and in 86/180 obligate carrier alleles (Grompe et al. 1994; Poudrier et al. 1996). The c.1062+5G>A variant was absent from 91 healthy controls and is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998). Based on the collective evidence, the c.1062+5G>A variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, 8821854, 8829657 and 8028615. Classification of NM_000137.2(FAH):c.1062+5G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
PS3, PM1, PM2, PP3, PP5
Comment:
Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin GA et al). Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R). The variant has been submitted to ClinVar as Pathogenic. Due to the above reasons it has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosinemia, type I, (MIM#276700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of Hep3B cells transfected with a minigene assay indicates that this variant causes exon 12 skipping, although additional products were observed. Due to these products, and the uncertainty regarding the use of minigene assays, the protein outcome of this splicing event is uncertain (PMID: 23895425). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (102 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both homozygous and compound heterozygous individuals with hereditary tyrosinemia (ClinVar, PMID: 30414057. PMID: 31574857). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
FAH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Comment:
Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain. | Couce ML | Medicine | 2019 | PMID: 31574857 |
| The Unique Spectrum of Mutations in Patients with Hereditary Tyrosinemia Type 1 in Different Regions of the Russian Federation. | Baydakova GV | JIMD reports | 2019 | PMID: 30414057 |
| The somatic FAH C.1061C>A change counteracts the frequent FAH c.1062+5G>A mutation and permits U1snRNA-based splicing correction. | Scalet D | Journal of human genetics | 2018 | PMID: 29497141 |
| Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles. | Yang H | Molecular genetics and metabolism reports | 2017 | PMID: 29326876 |
| Newborn Screening for Hereditary Tyrosinemia Type I in Québec: Update. | Giguère Y | Advances in experimental medicine and biology | 2017 | PMID: 28755192 |
| Tyrosinemia Type I. | Adam MP | - | 2017 | PMID: 20301688 |
| Type 1 Tyrosinaemia. | Mannion MA | Irish medical journal | 2016 | PMID: 27814443 |
| Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation. | Ijaz S | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 26565546 |
| Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1. | Angileri F | JIMD reports | 2015 | PMID: 25681080 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
| Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. | Mayorandan S | Orphanet journal of rare diseases | 2014 | PMID: 25081276 |
| Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I. | Pérez-Carro R | Clinical genetics | 2014 | PMID: 23895425 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| Identification of Novel Mutations in FAH Gene and Prenatal Diagnosis of Tyrosinemia in Indian Family. | Sheth JJ | Case reports in genetics | 2012 | PMID: 23193487 |
| Hereditary tyrosinaemia type I in Norway: incidence and three novel small deletions in the fumarylacetoacetase gene. | Bliksrud YT | Scandinavian journal of clinical and laboratory investigation | 2012 | PMID: 22554029 |
| Mutation spectrum of fumarylacetoacetase gene and clinical aspects of tyrosinemia type I disease. | Dursun A | JIMD reports | 2011 | PMID: 23430822 |
| 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 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| A minor alternative transcript of the fumarylacetoacetate hydrolase gene produces a protein despite being likely subjected to nonsense-mediated mRNA decay. | Dreumont N | BMC molecular biology | 2005 | PMID: 15638932 |
| 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 |
| Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I. | Elpeleg ON | Human mutation | 2002 | PMID: 11754109 |
| Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1. | Bergeron A | The Journal of biological chemistry | 2001 | PMID: 11278491 |
| Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes. | Poudrier J | Molecular genetics and metabolism | 1998 | PMID: 9705236 |
| 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 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Fumarylacetoacetase mutations in tyrosinaemia type I. | Rootwelt H | Human mutation | 1996 | PMID: 8829657 |
| Frequency of the IVS12 + 5G-->A splice mutation of the fumarylacetoacetate hydrolase gene in carriers of hereditary tyrosinaemia in the French Canadian population of Saguenay-Lac-St-Jean. | Poudrier J | Prenatal diagnosis | 1996 | PMID: 8821854 |
| Two novel mutations involved in hereditary tyrosinemia type I. | St-Louis M | Human molecular genetics | 1995 | PMID: 7757089 |
| A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I. | Grompe M | The New England journal of medicine | 1994 | PMID: 8028615 |
| Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I. | Grompe M | Human mutation | 1993 | PMID: 8318997 |
| - | - | - | - | PMID: 306090409 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FAH | - | - | - | - |
| http://www.ncbi.nlm.nih.gov/books/NBK1515/ | - | - | - | - |
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Text-mined citations for rs80338901 ...
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the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.