NM_000137.4(FAH):c.424A>G (p.Arg142Gly) AND Tyrosinemia type I

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 28, 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:: RCV001192778.7

Allele description [Variation Report for NM_000137.4(FAH):c.424A>G (p.Arg142Gly)]

NM_000137.4(FAH):c.424A>G (p.Arg142Gly)

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.424A>G (p.Arg142Gly)

HGVS:

NC_000015.10:g.80162305A>G
NG_012833.1:g.14307A>G
NM_000137.4:c.424A>GMANE SELECT
NM_001374377.1:c.424A>G
NM_001374380.1:c.424A>G
NP_000128.1:p.Arg142Gly
NP_001361306.1:p.Arg142Gly
NP_001361309.1:p.Arg142Gly
NC_000015.9:g.80454647A>G
NC_000015.9:g.80454647A>G
NM_000137.1:c.424A>G
NM_000137.2:c.424A>G

Protein change:

R142G

Links:

dbSNP: rs1420414848

NCBI 1000 Genomes Browser:

rs1420414848

Molecular consequence:

NM_000137.4:c.424A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374377.1:c.424A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374380.1:c.424A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361113	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 29, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27397503, 28755182 Citation Link,
SCV001981680	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004195909	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004297662	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27397503, 28492532

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, literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular Aspects of the FAH Mutations Involved in HT1 Disease.

Morrow G, Angileri F, Tanguay RM.

Adv Exp Med Biol. 2017;959:25-48. doi: 10.1007/978-3-319-55780-9_3. Review.

PubMed [citation]

PMID:: 28755182

Tyrosinemia Type I.

Sniderman King L, Trahms C, Scott CR.

2006 Jul 24 [updated 2017 May 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301688

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361113.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: FAH c.424A>G (p.Arg142Gly) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.424A>G has been reported in the literature in a family with three affected siblings (homozygous for the variant) who developed chronic liver disease and hepatocellular carcinoma without elevated tyrosine or succinylacetone (Blackburn_2016). The unaffected parents and two other unaffected siblings were determined to be carriers of the variant. These data indicate that the variant is very likely to be associated with disease. At least one publication showed that this variant results in loss of enzyme activity (Blackburn_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 GeneReviews, SCV001981680.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Baylor Genetics, SCV004195909.1

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

From Invitae, SCV004297662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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. Experimental studies have shown that this missense change affects FAH function (PMID: 27397503). 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 not expected to disrupt FAH protein function. ClinVar contains an entry for this variant (Variation ID: 928613). This missense change has been observed in individual(s) with clinical features of FAH-related conditions (PMID: 27397503). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 142 of the FAH protein (p.Arg142Gly).

#	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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