ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.1009G>A (p.Gly337Ser) (rs80338900)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
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
Invitae RCV000012644 SCV000828028 pathogenic Tyrosinemia type I 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 337 of the FAH protein (p.Gly337Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs80338900, ExAC 0.03%). This variant has also been reported as homozygous or in combination with other FAH variants in individuals affected with tyrosinemia type 1 (PMID: 8076937, 9633815, 24756054, 22554029). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 11869). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this missense change causes aberrant splicing of FAH mRNA in patient fibroblasts (PMID: 8076937). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000012644 SCV001163762 pathogenic Tyrosinemia type I 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.
OMIM RCV000012644 SCV000032879 pathogenic Tyrosinemia type I 1995-02-01 no assertion criteria provided literature only
GeneReviews RCV000012644 SCV000040446 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000012644 SCV001454598 pathogenic Tyrosinemia type I 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.