Submissions for variant NM_000277.3(PAH):c.800A>T (p.Gln267Leu)

dbSNP: rs778154939

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000210763	SCV000852111	uncertain significance	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD ( 0.00001, 0.000004063); PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.975; PP4_Moderate: Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup. (PMID:21307867; PMID:24078561; PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210763	SCV002231502	pathogenic	Phenylketonuria	2021-10-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 21307867, 24078561, 26503515, 31355225, 32668217). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln267 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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: 225135). This variant is present in population databases (rs778154939, ExAC 0.01%). This sequence change replaces glutamine with leucine at codon 267 of the PAH protein (p.Gln267Leu). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and leucine.
Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital	RCV000210763	SCV000266852	likely pathogenic	Phenylketonuria	2013-10-01	no assertion criteria provided	clinical testing