ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.520C>T (p.Arg174Ter)

dbSNP: rs781496816
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Total submissions: 6
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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 2020-04-15 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 25681080, 23225041, 9101289, 9633815, 8723690, 23430822, 30414057)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2023-12-04 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. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). This variant is present in population databases (rs781496816, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with tyrosinemia type I (PMID: 8723690, 23225041, 23430822). ClinVar contains an entry for this variant (Variation ID: 188751). 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.
Baylor Genetics RCV000169065 SCV004195890 pathogenic Tyrosinemia type I 2023-07-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169065 SCV001454590 pathogenic Tyrosinemia type I 2020-09-16 no assertion criteria provided clinical testing

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