Submissions for variant NM_000277.3(PAH):c.1278T>C (p.Asn426=)

gnomAD frequency: 0.04425  dbSNP: rs59326968

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000400696	SCV000852128	benign	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.16641; BP4: no impact on gene in SIFT, Polyphen2, MutationTaster. 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: (BA1, BP4).
Eurofins Ntd Llc (ga)	RCV000078509	SCV000110365	benign	not specified	2012-10-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078509	SCV000303442	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000400696	SCV000375559	benign	Phenylketonuria	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000400696	SCV000629178	benign	Phenylketonuria	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000088823	SCV000696435	benign	not provided	2017-07-31	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1278T>C (p.Asn426Asn) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1666/121610 control chromosomes (104 homozygotes), predominantly in the African cohort at a frequency of 0.14655 (1525/10406). This frequency is about 19 times the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057), suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. A publication, Acosta_2001, classifies the variant as a polymorphism, along with multiple clinical diagnostic laboratories classify the variant as "likely benign/benign." Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088823	SCV000888342	benign	not provided	2021-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000088823	SCV001872489	benign	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000088823	SCV005235484	benign	not provided		criteria provided, single submitter	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088823	SCV000119414	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000400696	SCV001458994	benign	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing