Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001240020 | SCV001412940 | uncertain significance | Tyrosinemia type I | 2022-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 398 of the FAH protein (p.Gly398Glu). This variant is present in population databases (rs141946827, gnomAD 0.03%). 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: 965540). 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 not expected to disrupt FAH protein function. Experimental studies have shown that this missense change affects FAH function (PMID: 30954369). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002271635 | SCV002556305 | uncertain significance | not specified | 2022-05-27 | criteria provided, single submitter | clinical testing | Variant summary: FAH c.1193G>A (p.Gly398Glu) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domain (IPR011234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FAH causing Tyrosinemia Type 1 (0.00015 vs 0.0025), allowing no conclusion about variant significance. c.1193G>A has been reported in the literature in one compound heterozygous individual affected with Tyrosinemia Type 1 (Morrow_2019). The variant was found occuring in cis with a second missense variant (c.775G>C). Functionally, the variant of interest had 42-52% activity when expressed in HeLa cells, suggesting it is a significant contributor to patient phenotype. The in cis variant (c.775G>C) did not appreciably impact protein function on its own (65-95% activity). However, in combination, these two variants reduced FAH activity even further to 24-26% (Morrow_2019). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Fulgent Genetics, |
RCV001240020 | SCV002785171 | uncertain significance | Tyrosinemia type I | 2024-03-18 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV001240020 | SCV002089850 | uncertain significance | Tyrosinemia type I | 2020-04-21 | no assertion criteria provided | clinical testing |