Submissions for variant NM_000277.3(PAH):c.1055del (p.Gly352fs)

dbSNP: rs62516094

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000267428	SCV000852166	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4).
Eurofins Ntd Llc (ga)	RCV000088729	SCV000343399	pathogenic	not provided	2016-06-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088729	SCV000601706	pathogenic	not provided	2016-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000267428	SCV000696423	pathogenic	Phenylketonuria	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The c.1055delG (p.Gly352Valfs) variant in PAH gene is a frameshift change that results in the loss of ~162 amino acids of the PAH protein (~11%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present at a low frequency in the large control population datasets of ExAC (8.351e-06; 1/119744 chrs tested). The c.1055delG has been reported in multiple affected individuals with biochemically confirmed PKU via published reports. This variant is associated with predominantly severe clinical phenotype and homozygous patients are non-responsive to BH4 therapy. Lastly, it is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Counsyl	RCV000267428	SCV000789345	pathogenic	Phenylketonuria	2017-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000267428	SCV000915568	pathogenic	Phenylketonuria	2018-08-14	criteria provided, single submitter	clinical testing	The PAH c.1055delG (p.Gly352ValfsTer48) variant is predicted to result in a frameshift and premature truncation of the protein. Across a selection of the available literature, the p.Gly352ValfsTer48 variant has been reported in at least 37 unrelated individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in 21 individuals, in a compound heterozygous state in 15 individuals, and in a heterozygous state in one individual in whom a second variant was not identified (Rozen et al. 1994; Daniele et al. 2009; Dahri et al. 2010; Jeannesson-Thivisol et al. 2015). Most of these cases showed a classic phenotype; 14 individuals who were severely affected displayed clinical symptoms due to delayed diagnosis and treatment. Control data are unavailable for the p.Gly352ValfsTer48 variant, which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. Based on the collective evidence, the p.Gly352ValfsTer48 variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000267428	SCV001583415	pathogenic	Phenylketonuria	2024-03-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly352Valfs*48) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PKU) (PMID: 7913581). ClinVar contains an entry for this variant (Variation ID: 102498). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000267428	SCV002512201	pathogenic	Phenylketonuria	2021-11-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong, PP1 supporting, PP4 supporting
Baylor Genetics	RCV000267428	SCV004201385	pathogenic	Phenylketonuria	2023-12-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000088729	SCV005326093	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34828281, 1301187, 24939588, 7545869, 21228398, 7913581, 19786003, 9781015, 9634518, 8069318, 33375644, 29749107, 33465300, 30375370, 10394930, 30829006, 19292873, 23430918, 26666653, 32668217, 27535533)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000267428	SCV005374481	pathogenic	Phenylketonuria	2024-09-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088729	SCV000119311	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000267428	SCV001463122	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing