Submissions for variant NM_000137.4(FAH):c.1062+5G>A

gnomAD frequency: 0.00028  dbSNP: rs80338901

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078135	SCV000109973	pathogenic	not provided	2017-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000078135	SCV000329344	pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Common pathogenic variant in patients with tyrosinemia type I from the French origin population of Canada or from western Europe (St-Louis et al, 1997); Functional analysis using a minigene found that c.1062+5 G>A results in exon skipping of exon 12 (Prez-Carro et al. 2014); This variant is associated with the following publications: (PMID: 26565546, 8028615, 27876694, 25087612, 23895425, 22975760, 25525159, 8318997, 27794060, 29497141, 29326876, 30414057, 30609409, 31568711, 34426522, 31589614, 33083013, 11754109, 9705236)
Illumina Laboratory Services, Illumina	RCV000012645	SCV000394056	pathogenic	Tyrosinemia type I	2017-04-27	criteria provided, single submitter	clinical testing	The FAH c.1062+5G>A variant is one of the most commonly detected pathogenic variants in patients with tyrosinemia type 1. The variant has been reported in at least nine studies in which it is found in a total of 336 patients, including in 47 patients in a homozygous state, in five patients in a compound heterozygous state and in 15 patients in a heterozygous state. The c.1062+5G>A variant was also detected in 11/395 blood spots from anonymous newborns from the Quebec area (Grompe et al. 1993; Grompe et al. 1994; St-Louis et al. 1995; Poudrier et al. 1996; Bergman et al. 1998; Elpeleg et al. 2002; Arranz et al. 2002; Perez-Carro et al. 2014; Mayorandan et al. 2014). The incidence of tyrosinemia is much higher in the Saguenay-Lac-St-Jean region of Quebec than in the rest of the world. In this region the c.1062+5G>A variant was detected in 62/68 patient alleles, and in 86/180 obligate carrier alleles (Grompe et al. 1994; Poudrier et al. 1996). The c.1062+5G>A variant was absent from 91 healthy controls and is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in aberrant splicing leading to the skipping of exon 12 of the FAH gene (Arranz et al. 2002; Perez-Carro et al. 2014) and loss of enzyme activity in patient fibroblasts (St-Louis et al. 1995; Bergman et al. 1998). Based on the collective evidence, the c.1062+5G>A variant is classified as pathogenic for tyrosinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012645	SCV000695441	pathogenic	Tyrosinemia type I	2017-05-02	criteria provided, single submitter	clinical testing	Variant summary: The FAH c.1062+5G>A variant involves the alteration of a highly conserved intronic nucleotide in intron 12. Mutation taster tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies have shown that this variant leads to aberrant splicing causing either insertion of a 105 base-pair fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13 (Hahn_1995, Perez_2014) as well as loss of enzymatic activity in patients cells (Bergeron _2001). The variant of interest has been found in a large and broad control population from ExAC in 48/114466 control chromosomes at an allele frequency of 0.0004193, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant is a known common pathogenic variant that causes tyrosinemia type I and is more commonly found in French Canadian population than the rest of the world (Grompe_1994; GeneReviews). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000012645	SCV000713107	pathogenic	Tyrosinemia type I	2017-04-06	criteria provided, single submitter	clinical testing	The c.1062+5G>A (NM_000137.2) variant in FAH has been reported in 14 homozygous and 2 compound heterozygous individuals with Tyrosinemia type I (Grompe 1993, B liksrud 2012, Mayorandan 2014, and Mannion 2016). This variant has also been rep orted in ClinVar (Variation ID#11870) by multiple laboratories as pathogenic. Th is variant has been identified in 0.065% (41/63,022) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 80338901). In vitro splicing assays provide evidence that the c.1062+5G>A varian t impacts splicing (Perez-Carro 2014). Biallelic loss of function of the FAH gen e has been associated with Tyrosinemia type I. In summary, this variant meets c riteria to be classified as pathogenic for Tyrosinemia type I in an autosomal re cessive manner based upon functional evidence and its occurrence in individuals with this disease.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000012645	SCV000746930	pathogenic	Tyrosinemia type I	2017-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012645	SCV000826047	pathogenic	Tyrosinemia type I	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the FAH gene. It does not directly change the encoded amino acid sequence of the FAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338901, gnomAD 0.07%). This variant has been observed in individuals with hereditary tyrosinemia type 1 (PMID: 8318997, 23895425, 26565546). It is commonly reported in individuals of French-Canadian ancestry (PMID: 23193487, 28755192). ClinVar contains an entry for this variant (Variation ID: 11870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000012645	SCV000893383	pathogenic	Tyrosinemia type I	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012645	SCV001163764	pathogenic	Tyrosinemia type I	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000012645	SCV001193867	pathogenic	Tyrosinemia type I	2019-11-12	criteria provided, single submitter	clinical testing	NM_000137.2(FAH):c.1062+5G>A is classified as pathogenic in the context of type I tyrosinemia. Sources cited for classification include the following: PMID 23895425, 21752152, 12203990, 22554029, 8318997, 8821854, 8829657 and 8028615. Classification of NM_000137.2(FAH):c.1062+5G>A 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.
CeGaT Center for Human Genetics Tuebingen	RCV000078135	SCV001249202	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	FAH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Centogene AG - the Rare Disease Company	RCV000012645	SCV001424411	pathogenic	Tyrosinemia type I		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078135	SCV001715123	pathogenic	not provided	2019-08-26	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP3, PP5
Revvity Omics, Revvity	RCV000012645	SCV002022273	pathogenic	Tyrosinemia type I	2023-03-31	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000012645	SCV002073255	pathogenic	Tyrosinemia type I		criteria provided, single submitter	clinical testing	Thec.1062+5 G>A variant is a common pathogenic variant in patients with tyrosinemia type I from theFrench origin population of Canada or from western Europe (Lazarin GA et al). Functional analysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro R). The variant has been submitted to ClinVar as Pathogenic. Due to the above reasons it has been classified as Pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000078135	SCV002818245	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000012645	SCV004013440	pathogenic	Tyrosinemia type I		criteria provided, single submitter	not provided
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000078135	SCV004026906	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407317	SCV004113967	pathogenic	FAH-related disorder	2023-08-22	criteria provided, single submitter	clinical testing	The FAH c.1062+5G>A variant is predicted to interfere with splicing. This variant has been well documented to be causative for tyrosinemia type I (also referred to as IVS12+5G>A; Grompe and al-Dhalimy. 1993. PubMed ID: 8318997; Pérez-Carro et al. 2014. PubMed ID: 23895425) and is particularly prevalent in the French Canadian and Northern European populations (Poudrier et al. 1996. PubMed ID: 8821854; Sheth et al. 2012. PubMed ID: 23193487). Using minigene analysis, the c.1062+5G>A variant was shown to result in exon skipping (Pérez-Carro et al. 2014. PubMed ID: 23895425). This variant is interpreted as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11870/). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80472572-G-A). This variant is interpreted as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012645	SCV004698117	pathogenic	Tyrosinemia type I	2024-02-12	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012645	SCV005086468	pathogenic	Tyrosinemia type I	2023-12-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosinemia, type I, (MIM#276700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of Hep3B cells transfected with a minigene assay indicates that this variant causes exon 12 skipping, although additional products were observed. Due to these products, and the uncertainty regarding the use of minigene assays, the protein outcome of this splicing event is uncertain (PMID: 23895425). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (102 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both homozygous and compound heterozygous individuals with hereditary tyrosinemia (ClinVar, PMID: 30414057. PMID: 31574857). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000012645	SCV000032880	pathogenic	Tyrosinemia type I	1998-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000012645	SCV000040448	not provided	Tyrosinemia type I		no assertion provided	literature only	Northern European and French Canadian-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000012645	SCV000891501	pathogenic	Tyrosinemia type I	2017-12-30	no assertion criteria provided	curation
Natera, Inc.	RCV000012645	SCV001454599	pathogenic	Tyrosinemia type I	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000078135	SCV001554003	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078135	SCV001742656	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078135	SCV001953339	likely pathogenic	not provided		no assertion criteria provided	clinical testing