Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000690807 | SCV000818535 | pathogenic | Tyrosinemia type I | 2023-11-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the FAH protein (p.Gly248Arg). This variant is present in population databases (rs774861939, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 31568711; Invitae). ClinVar contains an entry for this variant (Variation ID: 570041). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330900 | SCV004037940 | uncertain significance | not specified | 2023-08-17 | criteria provided, single submitter | clinical testing | Variant summary: FAH c.742G>A (p.Gly248Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251494 control chromosomes (gnomAD). c.742G>A has been reported in the literature in a homozygous individual affected with Tyrosinemia Type 1 (example: Ibarra-Gonzalez_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31568711). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV000690807 | SCV004195887 | likely pathogenic | Tyrosinemia type I | 2023-12-29 | criteria provided, single submitter | clinical testing |