NM_000137.4(FAH):c.880A>C (p.Thr294Pro) AND Tyrosinemia type I

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 26, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001004596.6

Allele description [Variation Report for NM_000137.4(FAH):c.880A>C (p.Thr294Pro)]

NM_000137.4(FAH):c.880A>C (p.Thr294Pro)

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.880A>C (p.Thr294Pro)

HGVS:

NC_000015.10:g.80175058A>C
NG_012833.1:g.27060A>C
NM_000137.4:c.880A>CMANE SELECT
NM_001374377.1:c.880A>C
NM_001374380.1:c.880A>C
NP_000128.1:p.Thr294Pro
NP_001361306.1:p.Thr294Pro
NP_001361309.1:p.Thr294Pro
NC_000015.9:g.80467400A>C

Protein change:

T294P

Links:

dbSNP: rs370634385

NCBI 1000 Genomes Browser:

rs370634385

Molecular consequence:

NM_000137.4:c.880A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374377.1:c.880A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374380.1:c.880A>C - 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
SCV001163760	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003521739	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8723690, 9633815, 31300554, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001163760

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

SCV003521739

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 26, 2023)

germline

clinical testing

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

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Six novel mutations in the fumarylacetoacetate hydrolase gene of patients with hereditary tyrosinemia type I.

Timmers C, Grompe M.

Hum Mutat. 1996;7(4):367-9. No abstract available.

PubMed [citation]

PMID:: 8723690

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV001163760.1

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

From Invitae, SCV003521739.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

ClinVar contains an entry for this variant (Variation ID: 813491). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 294 of the FAH protein (p.Thr294Pro). This variant is present in population databases (rs370634385, gnomAD 0.007%). This missense change has been observed in individual(s) with tyrosinemia, type 1 (PMID: 8723690, 9633815). 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. Experimental studies have shown that this missense change affects FAH function (PMID: 31300554). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

ClinVar

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