ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.1069G>T (p.Glu357Ter) (rs121965075)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012646 SCV000631826 pathogenic Tyrosinemia type I 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu357*) in the FAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121965075, ExAC 0.004%). This variant has been reported in an individual affected with tyrosinemia type I (PMID: 8318997). ClinVar contains an entry for this variant (Variation ID: 11871). Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012646 SCV000695442 pathogenic Tyrosinemia type I 2016-11-03 criteria provided, single submitter clinical testing Variant summary: The FAH c.1069G>T (p.Glu357X) variant results in a premature termination codon, predicted to cause a truncated or absent FAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/121286 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). The variant has been reported in numerous affected indiivduals in the literature. In addition, one databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000012646 SCV000967665 pathogenic Tyrosinemia type I 2018-12-26 criteria provided, single submitter clinical testing The p.Glu357X variant in FAH has been reported in at least two compound heterozy gous individuals with Tyrosinemia type 1 (Grompe 1993, Kvittingen 1994, Ploos va n Amstel 1996). Sequencing of a patient mRNA showed a loss of expression of the transcript with this variant (Ploos van Amstel 1996). This variant has been iden tified in 9/129178 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID: 118 71). This nonsense variant leads to a premature termination codon at position 35 7, which is predicted to lead to a truncated or absent protein. Biallelic loss o f function of the FAH gene is an established disease mechanism in Tyrosinemia Ty pe 1. In summary, this variant meets criteria to be classified as pathogenic for Tyrosinemia Type 1 in an autosomal recessive manner based upon presence in affe cted individuals, low frequency in controls, and the predicted impact to the pro tein. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2, PS3_Supporting.
OMIM RCV000012646 SCV000032881 pathogenic Tyrosinemia type I 1993-01-01 no assertion criteria provided literature only
Counsyl RCV000012646 SCV000485134 likely pathogenic Tyrosinemia type I 2015-12-18 no assertion criteria provided clinical testing

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