ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.192+1G>T (rs786204683)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169491 SCV000220946 likely pathogenic Tyrosinemia type I 2014-12-10 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169491 SCV000917322 likely pathogenic Tyrosinemia type I 2020-02-24 criteria provided, single submitter clinical testing Variant summary: FAH c.192+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251492 control chromosomes. c.192+1G>T has been reported as part of a compound heterozygous genotype in the literature in at-least one individual affected with Tyrosinemia Type 1 (example, Bergman_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000169491 SCV001163751 pathogenic Tyrosinemia type I criteria provided, single submitter clinical testing
Invitae RCV000169491 SCV001576056 likely pathogenic Tyrosinemia type I 2020-09-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the FAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with tyrosinemia type I (PMID: 9633815). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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, 9633815). 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.

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