ClinVar Miner

Submissions for variant NM_000137.4(FAH):c.398A>T (p.His133Leu)

gnomAD frequency: 0.00002  dbSNP: rs775152764
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673595 SCV000798818 uncertain significance Tyrosinemia type I 2018-03-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000673595 SCV003443025 pathogenic Tyrosinemia type I 2024-06-26 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 133 of the FAH protein (p.His133Leu). This variant is present in population databases (rs775152764, gnomAD 0.02%). This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 21752152). ClinVar contains an entry for this variant (Variation ID: 557452). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAH protein function with a positive predictive value of 80%. This variant disrupts the p.His133 amino acid residue in FAH. Other variant(s) that disrupt this residue have been observed in individuals with FAH-related conditions (PMID: 12555948), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000673595 SCV005635315 likely pathogenic Tyrosinemia type I 2024-03-26 criteria provided, single submitter clinical testing
GeneDx RCV005255617 SCV005908439 uncertain significance not provided 2024-10-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25681080, 21752152, Romero2006[paper])
Baylor Genetics RCV000673595 SCV001163752 uncertain significance Tyrosinemia type I no assertion criteria provided clinical testing

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