Submissions for variant NM_000277.3(PAH):c.1242C>T (p.Tyr414=)

gnomAD frequency: 0.00779  dbSNP: rs1801152

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000541061	SCV000852150	benign	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2).
Eurofins Ntd Llc (ga)	RCV000174235	SCV000225502	benign	not specified	2015-02-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174235	SCV000303441	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000088814	SCV000515909	benign	not provided	2020-06-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 9781015)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541061	SCV000629183	benign	Phenylketonuria	2025-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088814	SCV000889564	benign	not provided	2018-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000174235	SCV000917926	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1242C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0074 in 277168 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.014 (in the gnomAD database), including 16 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Hyperphenylalaninemia phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000541061	SCV001268942	benign	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000088814	SCV004131787	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PAH: BP4, BP7, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000088814	SCV005235485	benign	not provided		criteria provided, single submitter	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088814	SCV000119405	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000174235	SCV002034185	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000174235	SCV002034918	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000541061	SCV002088619	benign	Phenylketonuria	2019-12-09	no assertion criteria provided	clinical testing