ClinVar Genomic variation as it relates to human health
NM_000137.4(FAH):c.192G>T (p.Gln64His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000137.4(FAH):c.192G>T (p.Gln64His)
Variation ID: 21054 Accession: VCV000021054.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q25.1 15: 80158170 (GRCh38) [ NCBI UCSC ] 15: 80450512 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Feb 14, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000137.4:c.192G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000128.1:p.Gln64His missense NM_001374377.1:c.192G>T NP_001361306.1:p.Gln64His missense NM_001374380.1:c.192G>T NP_001361309.1:p.Gln64His missense NC_000015.10:g.80158170G>T NC_000015.9:g.80450512G>T NG_012833.1:g.10172G>T P16930:p.Gln64His - Protein change
- Q64H
- Other names
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- Canonical SPDI
- NC_000015.10:80158169:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FAH | - | - |
GRCh38 GRCh37 |
699 | 767 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2013 | RCV000153218.14 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003445079.2 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000020126.32 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000825982.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 64 of the FAH protein (p.Gln64His). … (more)
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 64 of the FAH protein (p.Gln64His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80338894, gnomAD 0.05%). This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 7942842; Invitae). ClinVar contains an entry for this variant (Variation ID: 21054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in retention of 94 nucleotides of intron 2 and introduces a premature termination codon (PMID: 7942842). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 22, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000202692.7
First in ClinVar: Feb 02, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194213.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000137.2(FAH):c.192G>T(Q64H) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 22975760, 23430822, 23193487, 14691918, 9101289 … (more)
NM_000137.2(FAH):c.192G>T(Q64H) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 22975760, 23430822, 23193487, 14691918, 9101289 and 7942842. Classification of NM_000137.2(FAH):c.192G>T(Q64H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jul 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695443.1
First in ClinVar: May 03, 2013 Last updated: May 03, 2013 |
Comment:
Variant summary: The FAH c.192G>T (p.Gln64His) variant involves the alteration of a conserved nucleotide. This variant defies the donor-splice-site consensus sequence and it is considered … (more)
Variant summary: The FAH c.192G>T (p.Gln64His) variant involves the alteration of a conserved nucleotide. This variant defies the donor-splice-site consensus sequence and it is considered a splice-site mutation (Ijaz_JPEM_2015). Human 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). 5/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts the loss of the SF2/ASF binding motif and the creation of a splice donor site. Functional studies showed decreased or absent FAH mRNA and protein levels in HT1 patients with this variant The variant of interest has been found in a large, broad control population, ExAC in 8/121410 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant has been reported in multiple HT1 patients, in both homozygotes and heterozygotes (with unknown secondary allele)( Rootwelt_AJHG_1994, Rootwelt_HM_1996, Ijaz_JPEM_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893379.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163399.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001424412.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058702.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021054, PS1_S). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021054, PS1_S). Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product(PMID: 8829657, 7942842) (PS3_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (SPLICEAI: 0.9>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000060, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypertyrosinemia (present) , Cirrhosis of liver (present) , Abnormality of the liver (present)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tyrosinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101494.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The missense variant c.192G>T(p.Gln64His) in FAH gene has been observed in individual(s) with tyrosinemia type I (Rootwelt H et.al.,1994). The amino acid Gln at position … (more)
The missense variant c.192G>T(p.Gln64His) in FAH gene has been observed in individual(s) with tyrosinemia type I (Rootwelt H et.al.,1994). The amino acid Gln at position 64 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The p.Gln64His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.006009% is reported in gnomAD. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Gln64His in FAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic . (less)
Clinical Features:
Abnormality of the liver (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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T-substance anomaly
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171860.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001461574.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Tyrosinemia type I
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040449.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Pakistani-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Ethnicity/Population group: Pakistani
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Tyrosinemia Type I. | Adam MP | - | 2017 | PMID: 20301688 |
Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation. | Ijaz S | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 26565546 |
Geographical and Ethnic Distribution of Mutations of the Fumarylacetoacetate Hydrolase Gene in Hereditary Tyrosinemia Type 1. | Angileri F | JIMD reports | 2015 | PMID: 25681080 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Identification of Novel Mutations in FAH Gene and Prenatal Diagnosis of Tyrosinemia in Indian Family. | Sheth JJ | Case reports in genetics | 2012 | PMID: 23193487 |
Mutation spectrum of fumarylacetoacetase gene and clinical aspects of tyrosinemia type I disease. | Dursun A | JIMD reports | 2011 | PMID: 23430822 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. | Demers SI | Human pathology | 2003 | PMID: 14691918 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. | St-Louis M | Human mutation | 1997 | PMID: 9101289 |
Fumarylacetoacetase mutations in tyrosinaemia type I. | Rootwelt H | Human mutation | 1996 | PMID: 8829657 |
Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1. | Rootwelt H | American journal of human genetics | 1994 | PMID: 7942842 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FAH | - | - | - | - |
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Text-mined citations for rs80338894 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.