Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000801084 | SCV000940842 | pathogenic | Tyrosinemia type I | 2024-02-23 | criteria provided, single submitter | clinical testing | This variant results in the deletion of part of exon 6 (c.548_553+20del) 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 (rs768180953, gnomAD 0.01%). This variant has been observed in individual(s) with tyrosinemia type I (PMID: 12203990, 31568711). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as E6/I6del26. ClinVar contains an entry for this variant (Variation ID: 646736). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV000801084 | SCV004195868 | pathogenic | Tyrosinemia type I | 2024-01-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV004721612 | SCV005326913 | pathogenic | not provided | 2023-10-23 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as E6/I6del26; This variant is associated with the following publications: (PMID: 28755182, 25681080, 31568711, 12203990) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000801084 | SCV005422770 | likely pathogenic | Tyrosinemia type I | 2024-10-17 | criteria provided, single submitter | clinical testing | Variant summary: FAH c.548_553+20del26, also reported as E6/I6del26, involves a partial deletion of exon 6. This deletion spans a canonical splice-site and therefore is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of FAH function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251430 control chromosomes. c.548_553+20del26 has been reported in the presumed or confirmed compound heterozygous state in the literature in at least 2 individuals affected with Tyrosinemia Type 1 (example, Arranz_2002, Ibarra-Gonzlez_2019), including 1 individual carrying a pathogenic variant in trans. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in vitro (example, Arranz_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12203990, 31568711). ClinVar contains an entry for this variant (Variation ID: 646736). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV000801084 | SCV005635321 | pathogenic | Tyrosinemia type I | 2024-05-23 | criteria provided, single submitter | clinical testing |