ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.1062+5G>A (rs80338901)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078135 SCV000109973 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000078135 SCV000329344 pathogenic not provided 2017-06-16 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 (St-Louis and Tanguay, 1997). Functionalanalysis found that c.1062+5 G>A results in exon skipping of exon 12 (Pérez-Carro et al. 2014).Therefore, we interpret c.1062+5 G>A to be a pathogenic variant.
Illumina Clinical Services Laboratory,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.
Counsyl RCV000012645 SCV000485269 pathogenic Tyrosinemia type I 2016-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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,Partners HealthCare 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
Invitae RCV000012645 SCV000826047 pathogenic Tyrosinemia type I 2018-12-26 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs80338901, ExAC 0.07%). This variant is a founder mutation in French-Canadian population (PMID: 28755192) and is a prevalent FAH mutation in individuals with hereditary tyrosinemia type 1 (PMID: 23193487). ClinVar contains an entry for this variant (Variation ID: 11870). Experimental studies have shown that this intronic change causes aberrant RNA splicing in vitro (PMID: 23895425). Nucleotide substitutions within 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 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000012645 SCV000032880 pathogenic Tyrosinemia type I 1998-06-01 no assertion criteria provided literature only
GeneReviews RCV000012645 SCV000040448 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000012645 SCV000891501 pathogenic Tyrosinemia type I 2017-12-30 no assertion criteria provided curation

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.