Submissions for variant NM_000137.4(FAH):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00003  dbSNP: rs1057517972

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414667	SCV000491239	pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24016420, 24516753, 34426522, 31568711, 31300554)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000984171	SCV001227505	pathogenic	Tyrosinemia type I	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FAH mRNA. The next in-frame methionine is located at codon 71. This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with tyrosinemia type I (PMID: 21764616, 22802474, 24016420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372766). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984171	SCV001437349	pathogenic	Tyrosinemia type I	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: FAH c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250698 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals (several of them were homozygous) affected with Tyrosinemia Type 1 (example: Ibarra-Gonzalez_2019, Mohamed_2013, Imtiaz_2011). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Macias_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV003231470	SCV003929494	pathogenic	See cases	2023-02-28	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP5
CeGaT Center for Human Genetics Tuebingen	RCV000414667	SCV004137492	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	FAH: PM2, PM3, PM5, PP4:Moderate, PVS1:Moderate
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000984171	SCV005051762	pathogenic	Tyrosinemia type I	2024-02-01	criteria provided, single submitter	curation
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798829	SCV005420434	pathogenic	Tyrosinemia	2024-10-04	criteria provided, single submitter	research	PVS1,PP1,PM2,PM3,PM5,PP4
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000984171	SCV005442203	pathogenic	Tyrosinemia type I	2024-12-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000984171	SCV005635297	pathogenic	Tyrosinemia type I	2024-06-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000984171	SCV001132185	likely pathogenic	Tyrosinemia type I	2014-02-06	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984171	SCV001461573	pathogenic	Tyrosinemia type I	2020-09-16	no assertion criteria provided	clinical testing