Submissions for variant NM_000277.3(PAH):c.503del (p.Tyr168fs)

dbSNP: rs199475661

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000375882	SCV000852094	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. ExAC MAF: 0.00001.; PP4: Detected in PKU patient in international phase II clinical trial for sapropterin. (PMID:23430918). 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)	RCV000088953	SCV000330983	pathogenic	not provided	2015-09-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000375882	SCV000696451	pathogenic	Phenylketonuria	2016-12-06	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.503delA (p.Tyr168Serfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.526C>T, p.Arg176X; c.1089delG, p.Lys363fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121256 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in two unrelated patients who carry c.1222C>T/p.R408W (pathogenic) in trans (Sarkissian_2011 and one internal sample). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000375882	SCV003441009	pathogenic	Phenylketonuria	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102705). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia (PMID: 24368688). This variant is present in population databases (rs199475661, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr168Serfs*27) 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).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088953	SCV000119555	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000375882	SCV001455101	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing