Submissions for variant NM_000277.3(PAH):c.887A>G (p.Asp296Gly)

dbSNP: rs281865446

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106372	SCV001146748	uncertain significance	Phenylketonuria	2019-07-14	reviewed by expert panel	curation	The c.887A>G (p.Asp296Gly) variant in PAH has been reported in a proband with classic PKU (PMID: 26666653; PP4). The proband was heterozygous for variant; it was found with the known pathogenic (per ClinGen PAH Working Group; see ClinVar variant ID 577, c.1222C > T (p.Arg408Trp) allele; however, although the paper did say that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing. Thus, PM3 is downgraded to supporting. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent from ethnically diverse control databases (PM2). Another missense at the site, p.Asp296His, has been previously reported (BioPKU PAH0955) heterozygous in a Chinese proband with PKU; no further information appears to be provided in the manuscript or supplementary information regarding phenotype or second variant (PMID: 26503515). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3.
Invitae	RCV000106372	SCV002241460	pathogenic	Phenylketonuria	2021-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 120291). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26666653, 31355225). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 296 of the PAH protein (p.Asp296Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106372	SCV000143872	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.