ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs970505762
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Total submissions: 5
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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 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.

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