ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.707-1G>A

gnomAD frequency: 0.00002  dbSNP: rs149052294
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674905 SCV000800316 pathogenic Tyrosinemia type I 2018-06-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV000674905 SCV001163756 pathogenic Tyrosinemia type I 2024-02-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674905 SCV001591970 pathogenic Tyrosinemia type I 2024-11-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 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 (rs149052294, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with tyrosinemia type I (PMID: 9633815, 12203990). ClinVar contains an entry for this variant (Variation ID: 558607). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674905 SCV002572215 pathogenic Tyrosinemia type I 2022-08-22 criteria provided, single submitter clinical testing Variant summary: FAH c.707-1G>A 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 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes. c.707-1G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with Tyrosinemia Type 1 (example, Arranz_2002, Couce_2011, Imtiaz_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000674905 SCV005635334 pathogenic Tyrosinemia type I 2024-03-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV000674905 SCV002089832 pathogenic Tyrosinemia type I 2020-11-30 no assertion criteria provided clinical testing

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