Submissions for variant NM_000277.3(PAH):c.165del (p.Phe55fs)

dbSNP: rs199475566

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000642	SCV001146711	pathogenic	Phenylketonuria	2019-04-03	reviewed by expert panel	curation	The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1.
Eurofins Ntd Llc (ga)	RCV000078513	SCV000110369	pathogenic	not provided	2013-08-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000078513	SCV000239100	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Reported multiple times in various populations in association with a classic phenylketonuria (PKU) phenotype (Eigel et al. 1991; Alibakhshi et al. 2014; Groselj et al. 2012; Georgiou et al. 2012; Jeannesson-Thivisol et al. 2015; Sterl et al. 2013); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Described as not responsive to tetrahydrobiopterin therapy (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 23856132, 16198137, 12655553, 23500595, 1682235, 24048906, 22513348, 22330942, 26481238, 22526846, 24350308, 23357515, 21147011, 19609714, 19394257, 12655550, 10394930, 9781015, 18346471, 18299955, 26666653, 23430918, 32905092, 33465300, 32778825, 34828281, 35405047)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078513	SCV000601711	pathogenic	not provided	2016-12-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000642	SCV000696439	pathogenic	Phenylketonuria	2016-11-03	criteria provided, single submitter	clinical testing	Variant summary: The c.165delT (p.Phe55Leufs) variant in PAH gene is a frameshift change that results in the loss of the 393 amino acids of PAH (~85%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. According to the PAH enzymatic activity prediction it is expected to have a residual activity of 0%, which then will lead to elevated level of plasma Phe concentration. These predictions are in line with biochemical data observed in pts homozygous for c.165delT and presented with Classical PKU phenotype (MR, aphasia, elevated Phe plasma level ranging from 1477-2844umol/l). The variant is present in the large control population dataset of ExAC at a low frequency 0.000016 (2/121380 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0079) in this gene. The variant has been reported in multiple affected individuals homozygously or in compound heterozygosity via published reports and has been cited as Pathogenic by several reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000642	SCV001236492	pathogenic	Phenylketonuria	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe55Leufs*6) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs199475566, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (PMID: 1682235, 18346471, 23500595). ClinVar contains an entry for this variant (Variation ID: 611). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000078513	SCV004131791	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	PAH: PVS1, PM2
Baylor Genetics	RCV000000642	SCV004201370	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000000642	SCV000020792	pathogenic	Phenylketonuria	1991-10-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078513	SCV000119439	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000642	SCV000220853	pathogenic	Phenylketonuria	2019-07-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000642	SCV001459227	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing