Submissions for variant NM_000137.4(FAH):c.1210G>A (p.Gly404Ser)

gnomAD frequency: 0.00002  dbSNP: rs1297118863

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541997	SCV000631828	pathogenic	Tyrosinemia type I	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the FAH protein (p.Gly404Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 21117323, 27814443; 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: 459903). 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 with a negative predictive value of 80%. This variant disrupts the p.Gly404 amino acid residue in FAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001171904	SCV001334799	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000541997	SCV003842058	likely pathogenic	Tyrosinemia type I	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459903). A different missense change at the same codon (p.Gly404Arg) has been reported to be associated with FAH -related disorder (ClinVar ID: VCV001348938). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000541997	SCV004195878	likely pathogenic	Tyrosinemia type I	2023-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001171904	SCV005325762	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Reported in patients with tyrosinemia type I in published literature, including at least one who has a second FAH variant (Vondrckov et al., 2010; Angileri et al., 2015; Mannion et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21117323, 25681080, 27814443)