Submissions for variant NM_000277.3(PAH):c.440C>T (p.Pro147Leu)

dbSNP: rs199475694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000595460	SCV001146725	likely pathogenic	Phenylketonuria	2019-04-09	reviewed by expert panel	curation	The c.440C>T (p.Pro147Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 27121329, 26322415, 16527067, 30050108, 28982351). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variants p.R261Ter (PMID: 27121329); c.611A>G (PMID: 30050108); p.S70del (PMID: 28982351) (PM3_strong). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.
Eurofins Ntd Llc (ga)	RCV000088918	SCV000709067	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000595460	SCV000799981	likely pathogenic	Phenylketonuria	2018-05-21	criteria provided, single submitter	clinical testing
Invitae	RCV000595460	SCV004296182	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 147 of the PAH protein (p.Pro147Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26322415, 27121329, 31355225). ClinVar contains an entry for this variant (Variation ID: 102670). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro147 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10598814, 27121329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088918	SCV000119516	not provided	not provided		no assertion provided	not provided