Submissions for variant NM_000277.3(PAH):c.187A>C (p.Thr63Pro)

dbSNP: rs199475568

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000758120	SCV000886597	uncertain significance	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.187A>C (p.Thr63Pro) variant in PAH was detected in 1 Danish PKU patient (Phenylalanine > 600 umol/L). Other causes of hyperphenylalaninemia had been ruled out. (PMID: 8406445). It was in cis with a p.H64N variant (No assertion provided, ClinVar). The c.187A>C variant is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT:T,D; Polyphen2:D,P; MutationTaster:Disease causing; REVEL:0.768. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate.
GeneDx	RCV000088861	SCV001823370	likely pathogenic	not provided	2018-11-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 32668217, 11161839, 30037505)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088861	SCV000119456	not provided	not provided		no assertion provided	not provided