NM_000137.4(FAH):c.1A>G (p.Met1Val) AND Tyrosinemia type I

Clinical significance:Pathogenic (Last evaluated: Sep 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000984171.5

Allele description [Variation Report for NM_000137.4(FAH):c.1A>G (p.Met1Val)]

NM_000137.4(FAH):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)
HGVS:
  • NC_000015.10:g.80153055A>G
  • NG_012833.1:g.5057A>G
  • NM_000137.4:c.1A>GMANE SELECT
  • NM_001374377.1:c.1A>G
  • NM_001374380.1:c.1A>G
  • NP_000128.1:p.Met1Val
  • NP_000128.1:p.Met1Val
  • NP_001361306.1:p.Met1Val
  • NP_001361309.1:p.Met1Val
  • NC_000015.9:g.80445397A>G
  • NM_000137.2:c.1A>G
  • NM_000137.3:c.1A>G
Protein change:
M1V
Links:
dbSNP: rs1057517972
NCBI 1000 Genomes Browser:
rs1057517972
Molecular consequence:
  • NM_000137.4:c.1A>G - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001374377.1:c.1A>G - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001374380.1:c.1A>G - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_000137.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374377.1:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374380.1:c.1A>G - 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
SCV001132185Counsylno assertion criteria providedLikely pathogenic
(Feb 6, 2014)
unknownclinical testing

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

SCV001227505Invitaecriteria provided, single submitter
Pathogenic
(Aug 20, 2020)
germlineclinical testing

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

SCV001437349Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 21, 2020)
germlineclinical testing

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

Citation Link,

SCV001461573Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

Gene symbol: FAH. Disease: tyrosinaemia 1.

Arranz A, Rigante D, Antuzzi D, Riudor E.

Hum Genet. 2005 Dec;118(3-4):537. No abstract available.

PubMed [citation]
PMID:
16521249

Persistent coagulopathy during Escherichia coli sepsis in a previously healthy infant revealed undiagnosed tyrosinaemia type 1.

Georgouli H, Schulpis KH, Michelakaki H, Kaltsa M, Sdogou T, Kossiva L.

BMJ Case Rep. 2010 Dec 29;2010. doi:pii: bcr0720103150. 10.1136/bcr.07.2010.3150.

PubMed [citation]
PMID:
22802474
PMCID:
PMC3029516
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV001132185.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001227505.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change affects the initiator methionine of the FAH mRNA. The next in-frame methionine is located at codon 71. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and to segregate in families with tyrosinemia type I (PMID: 21764616, 22802474, 24016420). ClinVar contains an entry for this variant (Variation ID: 372766). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437349.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: FAH c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250698 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals (several of them were homozygous) affected with Tyrosinemia Type 1 (example: Ibarra-Gonzalez_2019, Mohamed_2013, Imtiaz_2011). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Macias_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. 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

From Natera, Inc., SCV001461573.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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