ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.782C>T (p.Pro261Leu) (rs80338898)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153220 SCV000202694 pathogenic not provided 2014-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000153220 SCV000321620 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing The P261L missense variant in the FAH gene is a common variant in patients with tyrosinemia type Iwho are of an Ashkenazi Jewish background (Elpeleg et al., 2002). This substitution occurs at aposition that is conserved across species, and in silico analysis predicts this variant is probablydamaging to the protein structure/function. In summary, we interpret this variant as pathogenic.
Counsyl RCV000020129 SCV000485944 likely pathogenic Tyrosinemia type I 2016-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020129 SCV000915695 pathogenic Tyrosinemia type I 2017-09-13 criteria provided, single submitter 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.
Invitae RCV000020129 SCV000937169 likely pathogenic Tyrosinemia type I 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 261 of the FAH protein (p.Pro261Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs80338898, ExAC 0.02%). This variant has been observed in individuals affected with hereditary tyrosinemia type 1 (PMID: 11754109, 9633815, 21764616, 15187789). ClinVar contains an entry for this variant (Variation ID: 21058). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews RCV000020129 SCV000040453 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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