ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.554-1G>T (rs80338895)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078138 SCV000232008 pathogenic not provided 2015-02-07 criteria provided, single submitter clinical testing
GeneDx RCV000078138 SCV000321623 pathogenic not provided 2016-05-04 criteria provided, single submitter clinical testing The c.554-1 G>T pathogenic variant in the FAH gene is a common variant in patients with tyrosinemia type I from central and western Europe (Rootwelt et al., 1996). This pathogenic variant destroys the canonical splice acceptor site in intron 6, and is expected to cause abnormal gene splicing.
Illumina Clinical Services Laboratory,Illumina RCV000012649 SCV000394049 pathogenic Tyrosinemia type I 2017-04-27 criteria provided, single submitter clinical testing The FAH c.554-1G>T variant, also known IVS6-1G>T, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.554-1G>T variant is a well described common FAH pathogenic variant, accounting for over 16% of tyrosinemia disease-associated alleles worldwide (Sniderman King et al. 2006; Angileri et al. 2015). Across a selection of the available literature, the c.554-1G>T variant has been reported in at least 71 patients including in 48 in a homozygous state, in 16 in a compound heterozygous state, and in seven in a heterozygous state in whom a second variant has not been detected (Rootwelt et al. 1996; Timmers et al. 1996; Bergman et al. 1998; Dreumont et al. 2001; Arranz et al. 2002; la Marca et al. 2011; Dursun et al. 2011; Laszlo et al. 2013; van Vliet et al. 2015; Mayorandan et al. 2014). The variant was absent from 270 control chromosomes but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies have shown that the variant results in an absence of FAH protein, undetectable FAH activity in patient liver cells and fibroblasts, and a complex pattern of aberrant splicing (Bergman et al. 1998; Arranz et al. 2002; Angileri et al. 2015). Based on the collective evidence and the potential impact of splice acceptor variants, the c.554-1G>T 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 RCV000012649 SCV000485274 pathogenic Tyrosinemia type I 2016-02-21 criteria provided, single submitter clinical testing
Invitae RCV000012649 SCV000631832 pathogenic Tyrosinemia type I 2018-12-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the FAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80338895, ExAC 0.03%). This variant is one of the most common in cases of tyrosinemia type 1 and it has been reported in multiple affected individuals both in the homozygous and in the compound heterozygous state (PMID: 8829657, 12203990, 11476670). ClinVar contains an entry for this variant (Variation ID: 11874). Experimental studies with RT-PCR on fibroblasts and tumor tissue from individuals with this variant have shown that this variant leads to aberrant splicing and exon skipping (PMID: 11476670). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012649 SCV000695445 pathogenic Tyrosinemia type I 2017-01-12 criteria provided, single submitter clinical testing Variant summary: The FAH c.554-1G>T variant involves the alteration of a conserved intronic nucleotide located in the canonical splice site at the junction of intron6/exon7 border. Mutation taster predicts a damaging outcome for this variant along with 5/5 splice prediction tools predicting the variant to eliminate the splice acceptor site. This variant was found in 13/121368 control chromosomes at a frequency of 0.0001071, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). This variant has been reported in several Tyrosemia type 1 patients either in homozygosity or compound heterozygosity with other potentially pathogenic FAH variant indicating pathogenicity of this variant. RT-PCR products amplified from total RNA extracted from cultured fibroblasts of a patient homozygous for IVS6-1G->T showed aberrant splicing pattern further supporting its deleterious impact. In addition, another variant affecting the same position, c.554-1G>C is reported in HGMD as a disease causing mutation. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Considering all evidence, the variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000012649 SCV000893381 pathogenic Tyrosinemia type I 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000012649 SCV000032884 pathogenic Tyrosinemia type I 1996-01-01 no assertion criteria provided literature only
GeneReviews RCV000012649 SCV000040450 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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