VCV000011873.16 - ClinVar

NM_000137.4(FAH):c.786G>A (p.Trp262Ter)

Germline

Classification

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.

(6)

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

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.786G>A (p.Trp262Ter)

Variation ID: 11873 Accession: VCV000011873.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q25.1 15: 80173093 (GRCh38) [ NCBI UCSC ] 15: 80465435 (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	May 3, 2013	Feb 14, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000137.4:c.786G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000128.1:p.Trp262Ter	nonsense
NM_001374377.1:c.786G>A	NP_001361306.1:p.Trp262Ter	nonsense
NM_001374380.1:c.786G>A	NP_001361309.1:p.Trp262Ter	nonsense
NC_000015.10:g.80173093G>A
NC_000015.9:g.80465435G>A
NG_012833.1:g.25095G>A

... more HGVS ... less HGVS

Protein change

W262*

Other names

Canonical SPDI

NC_000015.10:80173092:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Exome Aggregation Consortium (ExAC) 0.00010

Links

ClinGen: CA341149 Genetic Testing Registry (GTR): GTR000575414 OMIM: 613871.0009 dbSNP: rs80338899 VarSome

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
Gene	OMIM	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	721	789

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.
Tyrosinemia type I	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Nov 27, 2023	RCV000012648.20

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 (Nov 12, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Tyrosinemia type I Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193978.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (6) PubMed: 8723698‚ 8162054‚ 15465000‚ 7942842‚ 15638932‚ 8829657 Comment: NM_000137.2(FAH):c.786G>A(W262) is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 8723698, 8162054, 15465000, 7942842, 15638932 … (more) NM_000137.2(FAH):c.786G>A(W262) is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 8723698, 8162054, 15465000, 7942842, 15638932 and 8829657. Classification of NM_000137.2(FAH):c.786G>A(W262*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Sep 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tyrosinemia type I Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195915.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tyrosinemia type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756182.4 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 9101289‚ 9633815‚ 7942842‚ 8162054‚ 8829657 Comment: This sequence change creates a premature translational stop signal (p.Trp262) in the FAH gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp262) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is present in population databases (rs80338899, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with tyrosinemia type I in Scandinavia (PMID: 7942842, 8162054, 8829657). ClinVar contains an entry for this variant (Variation ID: 11873). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 1996)	no assertion criteria provided Method: literature only	TYROSINEMIA, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032883.4 First in ClinVar: Apr 04, 2013 Last updated: Jul 02, 2015	Publications: PubMed (2) PubMed: 8162054‚ 8723698 Comment on evidence: St-Louis et al. (1994) reported a stop mutation in the FAH gene (W262X) in 5 Finnish patients with hereditary tyrosinemia type I (TYRSN1; 276700). This … (more) St-Louis et al. (1994) reported a stop mutation in the FAH gene (W262X) in 5 Finnish patients with hereditary tyrosinemia type I (TYRSN1; 276700). This mutation seemed to predominate in the Finnish population, where it accounted for 95% of the alleles (19/20) in 10 affected patients tested (St-Louis et al. (1996)), and had not been found in any other population. The remaining allele carried the IVS12+5G-A splice site mutation (613871.0003) that is predominant in the French Canadian population but is also seen in patients of other origins. St-Louis et al. (1996) described a simple test for the 'Finnish' mutation. (less)
Pathogenic (Sep 01, 2020)	no assertion criteria provided Method: clinical testing	Tyrosinemia type I Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089836.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: literature only	Tyrosinemia type I Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040454.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301688‚ 25681080 BookShelf: NBK1515 BookShelf: NBK1515 Comment: Finnish-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015]. Ethnicity/Population group: Finnish

Comment:

NM_000137.2(FAH):c.786G>A(W262*) is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 8723698, 8162054, 15465000, 7942842, 15638932 and 8829657. Classification of NM_000137.2(FAH):c.786G>A(W262*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change creates a premature translational stop signal (p.Trp262*) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is present in population databases (rs80338899, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with tyrosinemia type I in Scandinavia (PMID: 7942842, 8162054, 8829657). ClinVar contains an entry for this variant (Variation ID: 11873). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Tyrosinemia Type I.	Adam MP	-	2017	PMID: 20301688
Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1.	Angileri F	JIMD reports	2015	PMID: 25681080
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
Cytoplasmic nonsense-mediated mRNA decay for a nonsense (W262X) transcript of the gene responsible for hereditary tyrosinemia, fumarylacetoacetate hydrolase.	Dreumont N	Biochemical and biophysical research communications	2004	PMID: 15465000
Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries.	Bergman AJ	Human mutation	1998	PMID: 9633815
Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview.	St-Louis M	Human mutation	1997	PMID: 9101289
Fumarylacetoacetase mutations in tyrosinaemia type I.	Rootwelt H	Human mutation	1996	PMID: 8829657
Simple detection of a (Finnish) hereditary tyrosinemia type 1 mutation.	St-Louis M	Human mutation	1996	PMID: 8723698
Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I.	St-Louis M	Human molecular genetics	1994	PMID: 8162054
Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1.	Rootwelt H	American journal of human genetics	1994	PMID: 7942842

Text-mined citations for rs80338899 ...

These citations are identified by LitVar using 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000137.4(FAH):c.786G>A (p.Trp262Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338899 ...