NM_000137.4(FAH):c.192G>T (p.Gln64His) AND Tyrosinemia type II

Germline classification:: Pathogenic (1 submission)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004576910.1

Allele description [Variation Report for NM_000137.4(FAH):c.192G>T (p.Gln64His)]

NM_000137.4(FAH):c.192G>T (p.Gln64His)

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.192G>T (p.Gln64His)

HGVS:

NC_000015.10:g.80158170G>T
NG_012833.1:g.10172G>T
NM_000137.4:c.192G>TMANE SELECT
NM_001374377.1:c.192G>T
NM_001374380.1:c.192G>T
NP_000128.1:p.Gln64His
NP_000128.1:p.Gln64His
NP_000128.1:p.Gln64His
NP_001361306.1:p.Gln64His
NP_001361309.1:p.Gln64His
NC_000015.9:g.80450512G>T
NM_000137.1:c.192G>T
NM_000137.2:c.192G>T
NM_000137.3:c.192G>T
P16930:p.Gln64His

Protein change:

Q64H

Links:

UniProtKB: P16930#VAR_005207; dbSNP: rs80338894

NCBI 1000 Genomes Browser:

rs80338894

Molecular consequence:

NM_000137.4:c.192G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374377.1:c.192G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374380.1:c.192G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Tyrosinemia type II (TYRSN2)
Synonyms:: KERATOSIS PALMOPLANTARIS WITH CORNEAL DYSTROPHY; OREGON TYPE TYROSINEMIA; TAT DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010160; MedGen: C0268487; Orphanet: 28378; OMIM: 276600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005061176	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005061176

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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

Details of each submission

From Neuberg Centre For Genomic Medicine, NCGM, SCV005061176.1

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

Description

The observed missense c.192G>T (p.Gln64His) variant in FAH gene has been reported in homozygous state in individuals affected with Tyrosinemia (Ijaz S et al. 2016). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (Rootwelt H et al. 1996). The p.Gln64His variant is present with an allele frequency of 0.006% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid change p.Gln64His in FAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 64 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. Computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 5, 2025

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