ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.520C>T (p.Arg174Ter) (rs781496816)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169065 SCV000220229 likely pathogenic Tyrosinemia type I 2014-04-09 criteria provided, single submitter literature only
GeneDx RCV000413278 SCV000491240 pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing The R174X nonsense variant has been reported in association with tyrosinemia type I Timmers et al. (1996). R174X was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret R174X to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169065 SCV000919311 pathogenic Tyrosinemia type I 2018-03-19 criteria provided, single submitter clinical testing Variant summary: FAH c.520C>T (p.Arg174X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.1069G>T (p.Glu357X)). The variant allele was found at a frequency of 4.1e-06 in 246500 control chromosomes (in gnomAD and publication data). c.520C>T has been reported in the literature in individuals affected with Tyrosinemia Type 1 (Timmers 1996, Heath 2002, Dursun 2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169065 SCV000935719 pathogenic Tyrosinemia type I 2018-07-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg174*) in the FAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781496816, ExAC 0.006%). This variant has been observed in several individuals affected with tyrosinemia type I (PMID: 8723690 , 23225041, 23430822). ClinVar contains an entry for this variant (Variation ID: 188751). Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). For these reasons, this variant has been classified as Pathogenic.

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