Submissions for variant NM_000137.4(FAH):c.782C>T (p.Pro261Leu)

gnomAD frequency: 0.00006  dbSNP: rs80338898

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153220	SCV000202694	pathogenic	not provided	2014-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000153220	SCV000321620	pathogenic	not provided	2021-05-07	criteria provided, single submitter	clinical testing	Functional studies found that this variant is associated with approximately 8% residual enzyme activity compared to wild-type and results in destabilization of the enzyme (Macias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25681080, 9633815, 11754109, 25087612, 27415407, 22975760, 21764616, 30414057, 31300554, 29625052, 31130284, 31998365, 31980526, 15187789, 31589614)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020129	SCV000695446	pathogenic	Tyrosinemia type I	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The FAH c.782C>T (p.Pro261Leu) variant located in the fumarylacetoacestase, C-terminal-related domain (via InterPro) causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with allele frequency of 16/121404, predominantly in the European (Non-Finnish), 15/66732 (1/4448), which does not exceed the estimated maximal expected allele frequency for a pathogenic FAH variant of 1/400. The variant of interest has been reported in multiple affected individuals in a homozygous state via publications. In addition, multiple reputable databases/clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000020129	SCV000893382	pathogenic	Tyrosinemia type I	2024-05-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020129	SCV000937169	pathogenic	Tyrosinemia type I	2024-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the FAH protein (p.Pro261Leu). This variant is present in population databases (rs80338898, gnomAD 0.4%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 9633815, 11754109, 21764616, 31998365, 35800472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21058). 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 expected to disrupt FAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000020129	SCV001163759	pathogenic	Tyrosinemia type I	2024-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020129	SCV001194012	likely pathogenic	Tyrosinemia type I	2019-10-18	criteria provided, single submitter	clinical testing	NM_000137.2(FAH):c.782C>T(P261L) is classified as likely pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 11754109, 9633815, 15187789, and 9633815. Classification of NM_000137.2(FAH):c.782C>T(P261L) is based on the following criteria: This variant 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.‚Äã
Illumina Laboratory Services, Illumina	RCV000153220	SCV003802807	pathogenic	not provided	2022-11-16	criteria provided, single submitter	clinical testing	The FAH c.782C>T (p.Pro261Leu) missense variant results in the substitution of proline at amino acid position 261 with leucine and is one of the common pathogenic variant in this gene (PMID: 20301688). Across a selection of the available literature, this variant has been identified in at least eleven individuals with tyrosinemia type 1, all in a homozygous state (PMID: 9633815; PMID: 11754109; PMID: 21764616). The highest frequency of this allele in the Genome Aggregation Database is 0.003664 in the Ashkenazi Jewish population (version 2.1.1). The variant accounts for more than 99% of the pathogenic variants in this population (PMID: 20301688). Site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations with the variant protein revealed that the p.Pro261Leu variant protein results in destabilized protein with <10% of enzymatic activity compared to wild-type FAH (PMID: 31300554). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.782C>T (p.Pro261Leu) variant is classified as pathogenic for tyrosinemia type 1.
Revvity Omics, Revvity	RCV000020129	SCV003831187	likely pathogenic	Tyrosinemia type I	2022-10-13	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000020129	SCV004804970	pathogenic	Tyrosinemia type I	2024-03-17	criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000020129	SCV006055778	pathogenic	Tyrosinemia type I	2023-03-09	criteria provided, single submitter	research
GeneReviews	RCV000020129	SCV000040453	not provided	Tyrosinemia type I		no assertion provided	literature only	Ashkenazi Jewish-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Illumina Laboratory Services, Illumina	RCV000020129	SCV000915695	pathogenic	Tyrosinemia type I	2017-09-13	flagged submission	clinical testing	The FAH c.782C>T (p.Pro261Leu) variant is one of the four most common variants seen in patients with tyrosinemia type I, and is often observed in affected individuals of Ashkenazi Jewish descent (Sniderman King et al. 2017). The p.Pro261Leu variant has been reported in three studies in which it is found in a homozygous state in seven Israeli individuals with tyrosinemia type I (Bergman et al. 1998; Elpeleg et al. 2002; Korman and Gutman 2004). Control data are unavailable for this variant, which is reported at a frequency of 0.00374 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Pro261Leu variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
PreventionGenetics, part of Exact Sciences	RCV004752715	SCV005362800	pathogenic	FAH-related disorder	2024-05-22	no assertion criteria provided	clinical testing	The FAH c.782C>T variant is predicted to result in the amino acid substitution p.Pro261Leu. This variant has previously been reported to be causative for autosomal recessive tyrosinemia type 1. It is one of the most common pathogenic variants in this gene, and functional studies support its pathogenicity (Bergman et al. 1998. PubMed ID: 9633815; Elpeleg et al. 2002. PubMed ID: 11754109; Angileri et al. 2015. PubMed ID: 25681080; Macias et al. 2019. PubMed ID: 31300554; OMIM #276700). This variant is reported in 0.37% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.