Submissions for variant NM_000137.4(FAH):c.192+1G>T

dbSNP: rs786204683

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169491	SCV000917322	likely pathogenic	Tyrosinemia type I	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: FAH c.192+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251492 control chromosomes. c.192+1G>T has been reported as part of a compound heterozygous genotype in the literature in at-least one individual affected with Tyrosinemia Type 1 (example, Bergman_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other 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	RCV000169491	SCV001163751	pathogenic	Tyrosinemia type I		criteria provided, single submitter	clinical testing
Invitae	RCV000169491	SCV001576056	pathogenic	Tyrosinemia type I	2023-03-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189085). Disruption of this splice site has been observed in individual(s) with tyrosinemia type I (PMID: 9633815). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the FAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815).
Myriad Genetics, Inc.	RCV000169491	SCV002060210	likely pathogenic	Tyrosinemia type I	2021-11-01	criteria provided, single submitter	clinical testing	NM_000137.2(FAH):c.192+1G>T is a canonical splice variant classified as likely pathogenic in the context of tyrosinemia type I. c.192+1G>T has been observed in cases with relevant disease (PMID: 9633815). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. c.192+1G>T has not been observed in population frequency databases. In summary, NM_000137.2(FAH):c.192+1G>T is a canonical splice variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Natera, Inc.	RCV000169491	SCV002089821	likely pathogenic	Tyrosinemia type I	2021-05-13	no assertion criteria provided	clinical testing