Submissions for variant NM_000137.4(FAH):c.1027G>T (p.Gly343Trp)

gnomAD frequency: 0.00006  dbSNP: rs970505762

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000699322	SCV000828027	pathogenic	Tyrosinemia type I	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 343 of the FAH protein (p.Gly343Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 12203990; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 576751). 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%. This variant disrupts the p.Gly343 amino acid residue in FAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21764616). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000733554	SCV000861633	likely pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000699322	SCV001163763	pathogenic	Tyrosinemia type I	2024-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000699322	SCV002816171	likely pathogenic	Tyrosinemia type I	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000699322	SCV004804388	pathogenic	Tyrosinemia type I	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: FAH c.1027G>T (p.Gly343Trp) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domian (IPR011234) of 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 1.2e-05 in 247234 control chromosomes (gnomAD). c.1027G>T has been reported in the literature in multiple individuals affected with Tyrosinemia Type 1 (Arranz_2002, Couce_2011, Couce_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant effect results in 11% of normal activity (Macias_2019). The following publications have been ascertained in the context of this evaluation (PMID: 12203990, 31574857, 21752152, 35800472, 31300554, NO_PMID). ClinVar contains an entry for this variant (Variation ID: 576751). Based on the evidence outlined above, the variant was classified as pathogenic.