Submissions for variant NM_000277.3(PAH):c.963C>T (p.Leu321=)

gnomAD frequency: 0.01582  dbSNP: rs61747292

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000721181	SCV000852147	benign	Phenylketonuria	2018-07-29	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 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, BP7, BS3_Supporting, BS2).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507684	SCV000601720	benign	not specified	2016-10-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000507684	SCV000729359	benign	not specified	2018-02-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000721181	SCV001012192	benign	Phenylketonuria	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000721181	SCV001271162	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507684	SCV001361062	benign	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.963C>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 0.0039 in 251262 control chromosomes, predominantly at a frequency of 0.053 within the African or African-American subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three ClinVar submissions from clinical diagnostic laboratories and an expert panel (ClinGen)(evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089175	SCV000119790	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000721181	SCV001463128	benign	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing