ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.81+2T>A

gnomAD frequency: 0.00001  dbSNP: rs772895065
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454161 SCV000538027 uncertain significance Tyrosinemia type I 2015-09-01 criteria provided, single submitter clinical testing The c.81+2T>A variant in the FAH gene is a novel variant at the canonical splice site and is predicted to affect the splice donor site in intron 1 leading to abnormal splicing. Splice site variants that result in the absence of the FAH enzyme represent a well-established mechanism of disease in tyrosinemia type 1. This variant has not been reported in the 1000 genomes and Exome Sequencing Project control population databases and has been seen at very low frequency in ExAc (0.003%). In addition, splice-site computational algorithms have predicted this variant to abrogate splicing. While we have provisionally classified this variant as likely pathogenic, splicing studies are necessary to confirm this interpretation. To confirm these findings, we recommend submission of another blood specimen from this individual for RNA analysis. Please note that specific collection criteria are required for this sample. For more details and instructions about sample collection (including a specimen collection kit), please contact our laboratory.
Counsyl RCV000454161 SCV000800760 likely pathogenic Tyrosinemia type I 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000454161 SCV001405609 likely pathogenic Tyrosinemia type I 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the FAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs772895065, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with FAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 402229). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Baylor Genetics RCV000454161 SCV001163398 likely pathogenic Tyrosinemia type I 2021-09-30 no assertion criteria provided clinical testing
Natera, Inc. RCV000454161 SCV002089817 likely pathogenic Tyrosinemia type I 2020-01-31 no assertion criteria provided clinical testing

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