ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.1A>G (p.Met1Val) (rs1057517972)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414667 SCV000491239 pathogenic not provided 2019-09-16 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24016420, 24516753, 31300554, 31568711)
Invitae RCV000984171 SCV001227505 pathogenic Tyrosinemia type I 2020-08-20 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 not present in population databases (ExAC no frequency). This variant has been observed in individuals and to segregate in families with tyrosinemia type I (PMID: 21764616, 22802474, 24016420). 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.
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

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