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NM_000137.4(FAH):c.1027G>T (p.Gly343Trp) AND Tyrosinemia type I

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Mar 6, 2024
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:
RCV000699322.12

Allele description [Variation Report for NM_000137.4(FAH):c.1027G>T (p.Gly343Trp)]

NM_000137.4(FAH):c.1027G>T (p.Gly343Trp)

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.1027G>T (p.Gly343Trp)
HGVS:
  • NC_000015.10:g.80180190G>T
  • NG_012833.1:g.32192G>T
  • NM_000137.4:c.1027G>TMANE SELECT
  • NM_001374377.1:c.1027G>T
  • NM_001374380.1:c.1027G>T
  • NP_000128.1:p.Gly343Trp
  • NP_001361306.1:p.Gly343Trp
  • NP_001361309.1:p.Gly343Trp
  • NC_000015.9:g.80472532G>T
  • NM_000137.2:c.1027G>T
Protein change:
G343W
Links:
dbSNP: rs970505762
NCBI 1000 Genomes Browser:
rs970505762
Molecular consequence:
  • NM_000137.4:c.1027G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374377.1:c.1027G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374380.1:c.1027G>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000828027Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 27, 2024)
germlineclinical testing

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

SCV001163763Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 6, 2024)
unknownclinical testing

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

SCV002816171Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 10, 2021)
unknownclinical testing

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

SCV004804388Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Jan 11, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of mutations causing hereditary tyrosinemia type I in patients of Middle Eastern origin.

Imtiaz F, Rashed MS, Al-Mubarak B, Allam R, El-Karaksy H, Al-Hassnan Z, Al-Owain M, Al-Zaidan H, Rahbeeni Z, Qari A, Meyer BF, Al-Sayed M.

Mol Genet Metab. 2011 Dec;104(4):688-90. doi: 10.1016/j.ymgme.2011.06.019. Epub 2011 Jun 30.

PubMed [citation]
PMID:
21764616

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000828027.6

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the FAH protein (p.Gly343Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 12203990; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 576751). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAH protein function with a positive predictive value of 80%. This variant disrupts the p.Gly343 amino acid residue in FAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21764616). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From Baylor Genetics, SCV001163763.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV002816171.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804388.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: FAH c.1027G>T (p.Gly343Trp) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domian (IPR011234) 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 1.2e-05 in 247234 control chromosomes (gnomAD). c.1027G>T has been reported in the literature in multiple individuals affected with Tyrosinemia Type 1 (Arranz_2002, Couce_2011, Couce_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant effect results in 11% of normal activity (Macias_2019). The following publications have been ascertained in the context of this evaluation (PMID: 12203990, 31574857, 21752152, 35800472, 31300554, NO_PMID). ClinVar contains an entry for this variant (Variation ID: 576751). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 17, 2024