Submissions for variant NM_000137.4(FAH):c.1203C>G (p.Tyr401Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226638	SCV003922525	likely pathogenic	Tyrosinemia type I	2023-03-18	criteria provided, single submitter	clinical testing	Variant summary: FAH c.1203C>G (p.Tyr401X) results in a premature termination codon and is predicted to cause a truncation of the encoded protein. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant disrupts the last 19 amino acids in the protein sequence. Pathogenic missense variants downstream of this truncation have been reported in ClinVar (e.g. ClinVar: 459903), suggesting that the terminal 19 amino acids are important for normal function. The variant was absent in 251416 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1203C>G in individuals affected with Tyrosinemia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003226638	SCV004195908	likely pathogenic	Tyrosinemia type I	2022-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV003226638	SCV004479617	pathogenic	Tyrosinemia type I	2023-04-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FAH protein in which other variant(s) (p.Val412Glu) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with FAH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr401*) in the FAH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the FAH protein.