Submissions for variant NM_000137.4(FAH):c.1009G>A (p.Gly337Ser)

gnomAD frequency: 0.00006  dbSNP: rs80338900

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000012644	SCV000220983	likely pathogenic	Tyrosinemia type I	2014-12-24	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012644	SCV000828028	pathogenic	Tyrosinemia type I	2024-12-12	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 337 of the FAH protein (p.Gly337Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80338900, gnomAD 0.02%). This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 8076937, 9633815, 22554029, 24756054). 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: 11869). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FAH protein function with a positive predictive value of 80%. Studies have shown that this missense change results in removing the first 50 nucleotides of exon 12, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 24756054). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000012644	SCV001163762	pathogenic	Tyrosinemia type I	2024-02-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012644	SCV001361111	pathogenic	Tyrosinemia type I	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: FAH c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR011234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. This prediction has been confirmed by a study, using fibroblast derived mRNA from a homozygous patient, which has demonstrated the variant creates a functional acceptor splice site within exon 12, resulting in aberrant splice products (Rootwelt_1994). The variant had an incomplete effect on splicing, as the full length product, coding for the missense protein, was also detected in comparable amounts to the aberrant splice products (Rootwelt_1994). Though in this study no immunoreactive FAH protein could be detected in patient fibroblasts (Rootwelt_1994), the authors later noted that the resulting protein with G337S has about 19-31 % of normal FAH activity (Rootwelt_1996). The variant allele was found at a frequency of 7.2e-05 in 248584 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FAH causing Tyrosinemia Type 1 (7.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.1009G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Tyrosinemia Type 1 (example: Rootwelt_1994, Rootwelt 1996, Haghighi-Kakhki_2014). These data indicate that the variant is very likely to be associated with disease. One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000012644	SCV002793382	pathogenic	Tyrosinemia type I	2021-11-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000012644	SCV003821915	pathogenic	Tyrosinemia type I	2023-06-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321481	SCV004026895	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003321481	SCV005908440	pathogenic	not provided	2024-10-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G337S results in greatly reduced enzyme activity compared to wildtype (PMID: 31300554); Published functional studies demonstrate G337S results in aberrant splicing by introducing an acceptor splice site within exon 12, thereby deleting the first 50 nucleotides of this exon (PMID: 8076937); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 7757089, 9101289, 25087612, 24756054, 29625052, 8076937, 31300554, 36964991, 36451132, 9633815)
OMIM	RCV000012644	SCV000032879	pathogenic	Tyrosinemia type I	1995-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000012644	SCV000040446	not provided	Tyrosinemia type I		no assertion provided	literature only	Scandinavian population-specific pathogenic variant resulting from founder effect or genetic drift [Angileri et al 2015].
Natera, Inc.	RCV000012644	SCV001454598	pathogenic	Tyrosinemia type I	2020-09-16	no assertion criteria provided	clinical testing