U.S. flag

An official website of the United States government

NM_000137.4(FAH):c.47A>T (p.Asn16Ile) AND Tyrosinemia type I

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jul 25, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000012640.5

Allele description [Variation Report for NM_000137.4(FAH):c.47A>T (p.Asn16Ile)]

NM_000137.4(FAH):c.47A>T (p.Asn16Ile)

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.47A>T (p.Asn16Ile)
HGVS:
  • NC_000015.10:g.80153101A>T
  • NG_012833.1:g.5103A>T
  • NM_000137.2:c.47A>T
  • NM_000137.4:c.47A>TMANE SELECT
  • NM_001374377.1:c.47A>T
  • NM_001374380.1:c.47A>T
  • NP_000128.1:p.Asn16Ile
  • NP_001361306.1:p.Asn16Ile
  • NP_001361309.1:p.Asn16Ile
  • NC_000015.9:g.80445443A>T
  • P16930:p.Asn16Ile
Protein change:
N16I; ASN16ILE
Links:
UniProtKB: P16930#VAR_005205; OMIM: 613871.0001; dbSNP: rs121965073
NCBI 1000 Genomes Browser:
rs121965073
Molecular consequence:
  • NM_000137.4:c.47A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374377.1:c.47A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374380.1:c.47A>T - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000032875OMIM
no assertion criteria provided
Pathogenic
(Oct 1, 1992)
germlineliterature only

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

SCV004030028Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Jul 25, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1.

Bergeron A, D'Astous M, Timm DE, Tanguay RM.

J Biol Chem. 2001 May 4;276(18):15225-31. Epub 2001 Jan 22.

PubMed [citation]
PMID:
11278491

Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.

Macias I, LaĆ­n A, Bernardo-Seisdedos G, Gil D, Gonzalez E, Falcon-Perez JM, Millet O.

J Biol Chem. 2019 Aug 30;294(35):13051-13060. doi: 10.1074/jbc.RA119.009367. Epub 2019 Jul 12.

PubMed [citation]
PMID:
31300554
PMCID:
PMC6721957
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000032875.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a French Canadian patient with type I hereditary tyrosinemia (TYRSN1; 276700), Phaneuf et al. (1992) demonstrated compound heterozygosity for an FAH allele that appeared not to be expressed in the liver of the proband and a second allele that carried a 47A-T transversion which substituted isoleucine for asparagine-16 (N16I). These findings demonstrated that there are at least 2 different tyrosinemia mutations in the French Canadian population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004030028.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: FAH c.47A>T (p.Asn16Ile) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Fumarylacetoacetase, N-terminal (IPR015377) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251278 control chromosomes (gnomAD). c.47A>T has been reported in the literature in an individual affected with Tyrosinemia Type 1 (Phaneuf_1992). These data suggest the variant may be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function, finding that the variant protein lacks enzymatic activity and shows aberrant aggregation in the insoluble fraction of cells (Phaneuf_1992, Bergeron_2001, Macias_2019). The following publications have been ascertained in the context of this evaluation (PMID: 1401056, 11278491, 31300554). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 3, 2023