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NM_000137.4(FAH):c.82-1G>A AND Tyrosinemia type I

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Jul 5, 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:
RCV000667011.5

Allele description [Variation Report for NM_000137.4(FAH):c.82-1G>A]

NM_000137.4(FAH):c.82-1G>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.82-1G>A
HGVS:
  • NC_000015.10:g.80158059G>A
  • NG_012833.1:g.10061G>A
  • NM_000137.4:c.82-1G>AMANE SELECT
  • NM_001374377.1:c.82-1G>A
  • NM_001374380.1:c.82-1G>A
  • NC_000015.9:g.80450401G>A
  • NM_000137.2:c.82-1G>A
Links:
dbSNP: rs1247460110
NCBI 1000 Genomes Browser:
rs1247460110
Molecular consequence:
  • NM_000137.4:c.82-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001374377.1:c.82-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001374380.1:c.82-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000791397Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Likely pathogenic
(May 9, 2017)
unknownclinical testing

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

Citation Link,

SCV002265070Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Sep 8, 2021)
germlineclinical testing

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

SCV004195894Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 5, 2023)
unknownclinical testing

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

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

Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I.

Pérez-Carro R, Sánchez-Alcudia R, Pérez B, Navarrete R, Pérez-Cerdá C, Ugarte M, Desviat LR.

Clin Genet. 2014 Aug;86(2):167-71. doi: 10.1111/cge.12243. Epub 2013 Aug 21.

PubMed [citation]
PMID:
23895425

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000791397.1

#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 Invitae, SCV002265070.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 551853). Disruption of this splice site has been observed in individual(s) with tyrosinemia type 1 (PMID: 23895425). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 1 of the FAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815).

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

From Baylor Genetics, SCV004195894.1

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

Last Updated: Feb 20, 2024