ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs1297118863
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 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 2023-08-20 criteria provided, single submitter clinical testing

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