Submissions for variant NM_000137.4(FAH):c.745C>A (p.Pro249Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003064290	SCV003443026	pathogenic	Tyrosinemia type I	2022-06-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FAH function (PMID: 31300554). 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. This missense change has been observed in individual(s) with tyrosinemia type 1 (PMID: 8723690; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 249 of the FAH protein (p.Pro249Thr).
Baylor Genetics	RCV003064290	SCV004195873	likely pathogenic	Tyrosinemia type I	2023-09-22	criteria provided, single submitter	clinical testing