Submissions for variant NM_000277.3(PAH):c.1089del (p.Lys363fs)

dbSNP: rs5030654

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169397	SCV000852154	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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).
Counsyl	RCV000169397	SCV000220793	likely pathogenic	Phenylketonuria	2014-10-14	criteria provided, single submitter	literature only
GeneDx	RCV000088751	SCV000568713	pathogenic	not provided	2022-02-17	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: 9792407, 17096675, 22513348, 8659548, 20920871, 21147011, 9781015, 26481238, 18299955, 28676969, 29499199, 32905092, 31589614, 32778825, 24048906)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169397	SCV000696425	pathogenic	Phenylketonuria	2016-10-14	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1089delG (p.Lys363Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous PKU and HPA patients and is absent in 121252 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088751	SCV000889561	pathogenic	not provided	2018-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169397	SCV000943570	pathogenic	Phenylketonuria	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys363Asnfs*37) 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 individuals with phenylketonuria (PMID: 8889590, 20920871, 21890392, 24048906). ClinVar contains an entry for this variant (Variation ID: 102518). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000088751	SCV001747663	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PAH: PVS1, PM2, PM3:Supporting, PP4
Fulgent Genetics, Fulgent Genetics	RCV000169397	SCV002788461	pathogenic	Phenylketonuria	2021-11-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000169397	SCV002822897	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169397	SCV004201365	pathogenic	Phenylketonuria	2024-03-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169397	SCV004848854	pathogenic	Phenylketonuria	2022-11-03	criteria provided, single submitter	clinical testing	The p.Lys363AsnfsX37 in PAH has been reported in at least 12 homozygous and 1 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Carducci 2020 PMID: 32905092, Zare-Karizi 2011 PMID: 20920871, Kostandyan 2011 PMID: 21890392, Alibakhshi 2014 PMID: 24048906). This variant was classified as Pathogenic on August 10, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 102518) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 363 and leads to a premature termination codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088751	SCV000119335	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169397	SCV001463120	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing