NM_000137.4(FAH):c.1062+5G>A AND Tyrosinemia type I
- Germline classification:
- Pathogenic (18 submissions)
- Last evaluated:
- Mar 30, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000012645.50
Allele description [Variation Report for NM_000137.4(FAH):c.1062+5G>A]
NM_000137.4(FAH):c.1062+5G>A
- Gene:
- FAH:fumarylacetoacetate hydrolase [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 15q25.1
- Genomic location:
- Preferred name:
- NM_000137.4(FAH):c.1062+5G>A
- Other names:
- IVS12+5 G>A
- HGVS:
- NC_000015.10:g.80180230G>A
- NG_012833.1:g.32232G>A
- NM_000137.2:c.[1062+5G>A]
- NM_000137.4:c.1062+5G>AMANE SELECT
- NM_001374377.1:c.1062+5G>A
- NM_001374380.1:c.1062+5G>A
- NC_000015.9:g.80472572G>A
- NM_000137.1:c.1062+5G>A
- NM_000137.2:c.1062+5G>A
- NM_000137.2:c.[1062+5G>A]
- NM_000137.3:c.1062+5G>A
- NM_000137.4:c.1062+5G>A
- c.1062+5G>A
This HGVS expression did not pass validation- Nucleotide change:
- IVS12DS, G-A, +5
- Links:
- OMIM: 613871.0003; dbSNP: rs80338901
- NCBI 1000 Genomes Browser:
- rs80338901
- Molecular consequence:
- NM_000137.4:c.1062+5G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001374377.1:c.1062+5G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001374380.1:c.1062+5G>A - intron variant - [Sequence Ontology: SO:0001627]
- Observations:
- 1
Condition(s)
- Name:
- Tyrosinemia type I (TYRSN1)
- Synonyms:
- Tyrosinemia type 1; Hepatorenal tyrosinemia; FAH deficiency; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0010161; MedGen: C0268490; Orphanet: 882; OMIM: 276700
-
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See more...Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000032880 | OMIM | no assertion criteria provided | Pathogenic (Jun 1, 1998) | germline | literature only | |
| SCV000040448 | GeneReviews | no classification provided | not provided | germline | literature only | |
| SCV000394056 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) | Pathogenic (Apr 27, 2017) | germline | clinical testing | |
| SCV000695441 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (May 2, 2017) | germline | clinical testing | PubMed (4) LabCorp Variant Classification Summary - May 2015.docx, |
| SCV000713107 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Apr 6, 2017) | germline | clinical testing | |
| SCV000746930 | Genomic Research Center, Shahid Beheshti University of Medical Sciences | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 18, 2017) | inherited | clinical testing | |
| SCV000826047 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 22, 2024) | germline | clinical testing | |
| SCV000891501 | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | no assertion criteria provided | Pathogenic (Dec 30, 2017) | unknown | curation | |
| SCV000893383 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 31, 2022) | unknown | clinical testing | |
| SCV001163764 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 30, 2024) | unknown | clinical testing | |
| SCV001193867 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) | Pathogenic (Nov 12, 2019) | unknown | clinical testing | |
| SCV001424411 | Centogene AG - the Rare Disease Company | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV001454599 | Natera, Inc. | no assertion criteria provided | Pathogenic (Sep 16, 2020) | germline | clinical testing | |
| SCV002022273 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 31, 2023) | germline | clinical testing | |
| SCV002073255 | Neuberg Centre For Genomic Medicine, NCGM | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV004013440 | Institute of Human Genetics, University Hospital of Duesseldorf | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | not provided | |
| SCV004698117 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 12, 2024) | unknown | clinical testing | |
| SCV005086468 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
| criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 20, 2023) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | not provided | 1 | 1 | not provided | not provided | not provided | clinical testing, literature only |
| not provided | unknown | yes | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing, not provided |
| not provided | inherited | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| Northern European, French Canadian | germline | unknown | not provided | not provided | not provided | not provided | not provided | literature only |
Citations
PubMed
Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes.
Poudrier J, Lettre F, Scriver CR, Larochelle J, Tanguay RM.
Mol Genet Metab. 1998 Jun;64(2):119-25.
- PMID:
- 9705236
Angileri F, Bergeron A, Morrow G, Lettre F, Gray G, Hutchin T, Ball S, Tanguay RM.
JIMD Rep. 2015;19:43-58. doi: 10.1007/8904_2014_363. Epub 2015 Feb 15.
- PMID:
- 25681080
- PMCID:
- PMC4501228
PMC
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.
Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424
- PMCID:
- PMC4544753
- PMID:
- 25741868
- DOI:
- 10.1038/gim.2015.30
Details of each submission
From OMIM, SCV000032880.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (4) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From GeneReviews, SCV000040448.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Northern European, French Canadian | not provided | not provided | not provided | literature only | PubMed (2) |
Description
Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Illumina Laboratory Services, Illumina, SCV000394056.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (9) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695441.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000713107.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (6) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | 1 | not provided | 1 | not provided | |
From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746930.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | inherited | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826047.7
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, SCV000891501.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Fulgent Genetics, Fulgent Genetics, SCV000893383.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Baylor Genetics, SCV001163764.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Myriad Genetics, Inc., SCV001193867.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Centogene AG - the Rare Disease Company, SCV001424411.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Natera, Inc., SCV001454599.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Revvity Omics, Revvity, SCV002022273.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Neuberg Centre For Genomic Medicine, NCGM, SCV002073255.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Institute of Human Genetics, University Hospital of Duesseldorf, SCV004013440.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | not provided | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Institute of Human Genetics, University of Leipzig Medical Center, SCV004698117.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086468.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
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
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Oct 20, 2024