Submissions for variant NM_000277.3(PAH):c.869A>T (p.His290Leu)

dbSNP: rs62642919

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106371	SCV001572877	uncertain significance	Phenylketonuria	2021-03-26	reviewed by expert panel	curation	The c.869A>T (p.His290Leu) variant in PAH has been reported in a proband with classic PKU (PMID: 26666653); BH4 deficiency does not appear to have been formally excluded (PP4). It was found with the pathogenic variant c.838G>A (p.Glu280Lys) (PM3_Supporting). The amino acid substitution is predicted damaging by multiple lines of computational evidence (PP3). It is absent from ethnically diverse control databases (PM2). Other missense variants at the site, including p.His290Arg, p.His290Tyr, and p.His290Gln are classified as Likely Pathogenic and Uncertain Significance. Thus, PM5 is not met. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3-supporting, PP3, PP4.
Invitae	RCV000106371	SCV004294279	pathogenic	Phenylketonuria	2023-02-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His290 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22526846, 29499199; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 290 of the PAH protein (p.His290Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 120290). 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 PAH protein function.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106371	SCV000143871	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.