NM_000137.4(FAH):c.726G>A (p.Trp242Ter) AND Tyrosinemia type I

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 31, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001004595.6

Allele description [Variation Report for NM_000137.4(FAH):c.726G>A (p.Trp242Ter)]

NM_000137.4(FAH):c.726G>A (p.Trp242Ter)

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.726G>A (p.Trp242Ter)

HGVS:

NC_000015.10:g.80173033G>A
NG_012833.1:g.25035G>A
NM_000137.4:c.726G>AMANE SELECT
NM_001374377.1:c.726G>A
NM_001374380.1:c.726G>A
NP_000128.1:p.Trp242Ter
NP_001361306.1:p.Trp242Ter
NP_001361309.1:p.Trp242Ter
NC_000015.9:g.80465375G>A
NM_000137.2:c.726G>A

Protein change:

W242*

Links:

dbSNP: rs1567118987

NCBI 1000 Genomes Browser:

rs1567118987

Molecular consequence:

NM_000137.4:c.726G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001374377.1:c.726G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001374380.1:c.726G>A - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001163758	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001383319	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25681080, 9101289, 9633815, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001163758

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001383319

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1.

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.

PubMed [citation]

PMID:: 25681080
PMCID:: PMC4501228

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV001163758.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001383319.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 813490). This premature translational stop signal has been observed in individual(s) with tyrosinemia, type 1 (PMID: 25681080). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp242*) 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).

#	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

Last Updated: Feb 20, 2024

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